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Adrenal gland and paraganglia
Reviewers: See individual topics
Revised: 23 March 2011, last major update February 2005
Copyright: (c) 2002-2011, PathologyOutlines.com, Inc.
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, produces steroid hormones aldosterone, cortisol and testosterone) and adrenal medulla (neuroectodermal, produces catecholamines)
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 aorta, inferior phrenic arteries and renal arteries; are drained by shorter right adrenal vein and longer left adrenal vein
Lymphatics only in capsule, not elsewhere
Gross drawings: (1) view from front; (2) view from behind
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
Micro images: fetal and adult cortex
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
Micro images: cross section; cortical layers #1; #2; #3; #4; various images (low and high power); fasciculata; reticularis; fasciculata, reticularis and medulla; reticularis lipid stain
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
Micro images: adrenal medulla; images 45-48 (low and high power)
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
Gross images: large lobulated adrenal glands
Micro: bilateral cytomegaly with large and pleomorphic nuclei and cytoplasmic nuclear pseudoinclusions; also medullary hyperplasia; variable hemorrhagic macrocysts
Micro images: adrenal cytomegaly
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
Gross images: markedly enlarged adrenal glands
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
Virtual slides: atrophy (caused not specified)
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
Virtual slides: Addison’s disease
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
Virtual slides: amyloidosis
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
Gross images: red-brown adrenal glands due to hemorrhage
Fatal meningococcemia in 10 month old boy, courtesy Dr. Eric L. Vey, Erie County Coroner’s Officer, Erie, PA (USA) – adrenal glands in situ; normal (top) and hemorrhagic (bottom) adrenal glands
Micro: hemorrhage, necrosis, fibrin deposition, neutrophilic infiltration of medulla and cortex; zona glomerulosa cells may be spared
Micro images: due to Capnocytophaga canimorsus
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
Gross images: bilateral cortical hyperplasia (bottom); nodular with variegated surface due to lipomatous metaplasia
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
Micro images: diffuse hyperplasia of adrenocortical cells; lipomatous metaplasia
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
Gross images: well circumscribed tumor
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
Micro images: (1) tumor cells resemble zona fasciculata; (2) compact cells arranged in nests #1; #2; (4) multinucleated cells; (5) focal atypia #1; #2; (7) figure 2A: cells have vacuolated cytoplasm; (8) melanA/A103: figure 1: adenoma is +; figure 2: pheochromocytoma is negative
Virtual slides: adenoma
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
Gross images: well circumscribed adenoma
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
Gross images: tan-yellow tumor, 1.3 cm
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
Micro images: (1) figure 1: nesting pattern separated by fine microvasculature; 2: numerous spironolactone bodies; (2) figure 1: spironolactone bodies; 2: Luxol fast blue+; 3: renal clear cell carcinoma
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)
Gross: multicentric, bilateral, up to 3 cm; fibrous capsule for larger nodules; yellow with brown discoloration; adjacent cortex is not atrophic
Micro: fasciculata type cells, occasional myelolipomatous change or ossification
Tumor cells packed with mitochondria with tubulovesicular cristae typical of steroid-producing cells
Rare; usually nonfunctioning, usually benign
Mean age 45 years, range 27-74 years
Confirm adrenocortical origin by immunoreactivity to 3-beta-hydroxysteroid dehydrogenase, the enzyme that converts pregnenolone to progesterone and dehydroepiandrosterone to androstenedione
Clinical behavior not entirely predictable; Weiss system for malignancy not applicable because all tumors have eosinophilic tumor cytoplasm, diffuse architecture and nuclear atypia; better to use criteria of mitotic activity, necrosis, invasion, MIB1 activity
Case reports: 55 year old woman with 13 cm tumor (Archives 2003;127:e167), retroperitoneal oncocytoma of apparent adrenocortical origin (Archives 2002;126:1118)
Gross: light to dark brown, solid, well circumscribed, up to 20 cm
Gross/Xray images (ectopic tumor): solid tumor with smooth external surface
Micro: alveolar, tubular or solid patterns composed exclusively of oncocytes (epithelial cells with abundant eosinophilic, granular cytoplasm and sparse lipid), nuclear atypia common; no/rare mitotic activity, no necrosis
Tumors of uncertain malignant potential: increased mitotic activity and necrosis, but no invasion
Micro images: (1) figure 1: solid tan-brown mass with variegated cut surface; 2: sheets of large polygonal cells with abundant eosinophilic granular cytoplasm and small central nucleus; 3: EM shows dense mitochondria with platelike cristae, scattered non-membrane bound electron-dense granules; (2) a: nests of cells with abundant, eosinophilic granular cytoplasm; b: PTAH+; (3) 3 beta-hydroxysteroid dehydrogenase immunohistology
Positive stains: keratin (CAM 5.2, AE3), anti-mitochondrial antibody, PTAH, NSE, synaptophysin, low MIB1 (except in tumors of uncertain malignant potential), variable vimentin
Negative stains: chromogranin A, EMA, S100, p53
EM: numerous mitochondria, with stacked tubulo-vesicular and lamellar cristae, smooth endoplasmic reticulum, lysosomes, small electron dense inclusions
DD: oncocytic carcinoma, oncocytic pheochromocytoma (chromogranin A+), adrenocortical tumors with focal oncocytic change, eosinophilic variants of renal cell carcinoma (EMA+, NSE-, synaptophysin-)
References: AJSP 1998;22:603; AJSP 1991;15:949 (3 cases)
Rare, <20 cases reported
Single mass of admixed population of adrenal cortical and medullary cells
By definition, excludes simultaneously occurring adrenocortical adenomas and pheochromocytomas, ACTH-producing pheochromocytomas with associated adrenocortical hyperplasia
May be a collision tumor
85% women, mean age 50 years, range 32-61 years
Usually present with Cushing’s syndrome that resolves after tumor excision
Benign behavior
Case reports: 55 year old woman with Cushing’s syndrome and incidental myelolipoma (Archives 2003;127:e329)
Micro: mixture of medullary pheochromocytoma cells (abundant, finely granular eosinophilic cytoplasm and round/oval nuclei with coarse chromatin) and adrenocortical tumor cells (clear cytoplasm)
Micro images: (1) mixture of adrenocortical cells and pheochromocytoma cells; (2) pheochromocytoma component with abundant, finely granular cytoplasm and round/oval nuclei; (3) adrenocortical adenoma component with clear cytoplasm; (4) tumor thrombosis and recanalization of vascular channels #1; #2; (6) pheochromocytoma cells are chromogranin+; (7) synaptophysin+; (8) neuron specific enolase+; (9) sustentacular cells are S100+; (10) A: sheets, nests and cords of polygonal cells with clear cytoplasm; B: adrenocortical cells have clear vacuolated cytoplasm and small dark nuclei; adrenal medullary cells have granular basophilic cytoplasm and variably sized nuclei; C/D: calretinin+ (brown) adrenocortical cells and chromogranin+ (blue) pheochromocytes of adrenal medullary origin
Other benign cortical lesions
Adenomatoid tumor of adrenal gland
Very rare; tumors often incidental
Mean age 41 years, range 31-64 years, 90% male
Benign; resembles adenomatoid tumors of genital tract
Case reports: 33 year old man with 2 cm tumor (Archives 2003;127:1633), tumor with prominent cystic component (Archives 1990;114:722), patient with hypertension and clinical impression of pheochromocytoma (Archives 1990;114:725), 51 year old man with tumor and micronodular adrenal cortical hyperplasia (Hum Path 2003;34:818)
Gross: 1-4 cm, originates within adrenal gland, well-circumscribed, white-tan-gray, may have cystic structures
Micro: adenoid, angiomatoid, cystic and solid patterns of anastomosing glands and tubules of variable size lined by epithelioid and flattened cells; cells have low nuclear/cytoplasmic ratio, no mitotic activity; involves adrenal cortex, often medulla and often extends into adjacent adipose tissue with signet-ring like cells
Positive stains: calretinin, AE1/AE3, CAM 5.2, CK7, vimentin, CK5/6 (weak)
Negative stains: CK20, CD15, CD31, CD34, MOC31, CEA, MIB1 (low activity)
Molecular: diploid or tetraploid
EM: well formed desmosomes, extensively developed microvilli
DD: hemangioma, angiosarcoma, lymphangioma, malignant mesothelioma, yolk sac tumor, metastatic adenocarcinoma (including signet-ring cell), adrenal cyst
References: AJSP 2003;27:969; Mod Path 1996;9:1046
May produce mass or flank pain, or incidental finding on MRI or CT scans
Incidence of 0.06% at autopsy
Usually women
Case reports: 61 year old woman with incidental cyst containing ectopic thyroid tissue (Case of Week #188)
Treatment: excision
Gross: up to 30 cm, usually unilateral with irregular thick fibrous wall and calcifications; often yellow, residual adrenocortical tissue in wall
DD: cystic degeneration of adrenocortical neoplasm
References: Archives 1985;109:377
Bronchogenic cyst in retroperitoneum
Case report at Archives 1991;115:1057
Endothelial (vascular) cyst
See also hemorrhagic cyst below
45% of adrenal cysts
8% bilateral, 2/3 female
Gross: up to 50 cm, multiloculated with serous fluid
Gross images: 36 cm cyst #1; #2; #3
Micro: endothelial lining, may have residual adrenocortical tissue in wall
Micro images: (1) wall of hyalinized fibrous tissue #1; #2; (3) elastic stain shows elastic tissue within wall; (4) focal lining of flattened endothelial cells determines diagnosis of endothelial cyst; (5) organizing clot; (6) nests of trapped adrenocortical tissue; (7) vascular channels within fibrous wall
Positive stains: collagen type IV+, weak staining for factor VIII related antigen
Epithelial lined (true) cyst
Rare
May be derived from mesothelial structures
Either retention cysts, embryonal cysts or arising within adrenocortical adenomas (Hum Path 1989;20:491)
Micro: single layer of keratin+ cells
Hemorrhagic cyst (pseudocyst)
39% of adrenal cysts
Usually women, median age 41 years
May be associated with Beckwith-Wiedemann syndrome
Actually an endothelial (vascular) cyst or perhaps lymphangioendothelial cyst with subsequent hemorrhage, fibrosis and hemosiderin deposition; enlargement is due to hemorrhage and fluid accumulation
Gross: 2-10 cm or large
Micro: hyalinized fibrous capsule containing clotted blood, residual adrenocortical tissue and thin walled vascular channels in wall but no identifiable cyst lining
Positive stains: collagen type IV (strong), factor VIII related antigen, CD34, laminin
References: Archives 1986;110:121; Hum Path 1989;20:660; Mod Path 1997;10:530; AJSP 1989;13:740 (endothelial cysts and pseudocyts)
Lymphangioma
Rare (0.06% incidence)
Case report of 22 year old woman with 4 cm mass (Archives 2004;128:713)
Micro: thin walled cyst with smooth lining and flattened endothelial cells (CD31+)
Parasitic cyst
Usually echinococcal, often incidental
80% are pseudocysts, also endothelial cysts (17.5%) or epithelial cysts (2.5%)
Case reports: visceral leishmaniasis (Archives 2000;124:1553)
Micro: wall contains many eosinophils, also evidence of parasite
Micro images: visceral leishmaniasis - 1A: large cystic mass by CT scan; 1B: large adrenal gland mass compressing kidney; 2A: adrenal mass is semicystic with hemorrhage and necrosis; 2B: clotted blood and thin-walled endothelial channels; 3A/B: cyst wall has Leishmania amastigotes within macrophages and giant cells
DD: degeneration of adrenal neoplasm (grossly)
References: Hum Path 2000;31:75
Present in half of autopsied patients
Associated with chronic pyelonephritis
Micro: focal lymphoplasmacytic infiltrate in adrenal cortex
DD: Addison’s disease
Usually cavernous, detected incidentally at autopsy
Solitary
DD: adrenal cortical adenoma with degeneration and secondary vascular changes
Case reports: 6 week old infant involving adrenal gland and colon (Archives 1975;99:198); adult woman with E. coli infection (J Clin Path 1981;34:606)
Massive macronodular adrenal cortical disease
ACTH independent, may involve only a single gland
Bimodal age distribution: newborns (associated with McCune-Albright syndrome) and age 40+; rarely familial
Gross: glands up to 180g together, nodules up to 4 cm, non-nodular cortex may be atrophic
Micro: clear cells or compact cells
DD: neoplasm
Rare, benign, usually solitary tumor composed of hematopoietic precursor cells and mature fat
Usually an incidental autopsy finding (0.1 to 0.2% of cases) or incidental CT / MRI finding
Not associated with hematologic disorders; nonfunctioning
Most patients are obese adults (mean age 50 years)
May have areas of fibromyxoid degeneration resembling low-grade fibromyxoid sarcomas
Focal myelolipomatous change also in adrenocortical hyperplasia and tumors; usually incidental (Archives 1994;118:895)
May be metaplastic change in reticuloendothelial cells of blood capillaries in response to necrosis, infection or stress
Treatment: follow up or excision if symptomatic
Case reports: 70 year old woman with 52 year history of abdominal mass and 5 kg tumor (Archives 1981;105:532), 66 year old woman with 8 cm tumor (Archives 2004;128:703), bilateral giant tumors (Archives 1995;119:283), patient with congenital adrenal hyperplasia and giant adrenal tumor (AJSP 1979;3:109), association with 17-hydroxylase deficiency (Archives 1985;109:1116), myelolipoma and ganglioneuroma of adrenal medulla (Archives 2002;126:736), with subclinical Cushing’s disease (Archives 1997;121:735), arising in spleen (Archives 1995;119:561), giant extra-adrenal tumor (Archives 1994;118:188)
Gross: nonencapsulated, bright yellow adipose-like tissue with hemorrhagic foci (contains marrow tissue); may be up to 5 kg
Gross images: 24 cm tumor #1; #2
Micro: mature islands of hematopoietic cells and mature fat; larger tumors may have hemorrhage, necrosis, calcification, cyst formation
Micro images: (1) classic tumor #1; #2; (3) mature adipose and hematopoietic cells-various images; (4) with ganglioneuroma
DD: myelolipomatous change in cortical adenomas or cortical hyperplasia; also liposarcoma, myxoid malignant fibrous histiocytoma, extramedullary hematopoietic tumors, angiomyolipoma, teratoma
Also called stromal spindle nodules
Present in 5% of women (usually postmenopausal) undergoing adrenalectomy for metastatic breast carcinoma, rare in men
May be due to metaplasia from adrenal capsule mesenchymal cells due to unopposed pituitary gonadotropin during menopause
Usually no clinical significance
Case reports: virilizing Leydig cell adenoma in oophorectomized postmenopausal woman (AJSP 1986;10:816), 59 year old woman with virilizing ganglioneuroma (AJSP 1983;7:699), 49 year old woman with ovarian thecal metaplasia in adrenal gland, adrenocortical adenoma and pancreatic tissue with nesidiodysplasia (Archives 2004;128:1294), incidental finding at autopsy in 77 year old man with acquired bilateral testicular atrophy, probably due to prior bilateral inguinal herniorrhaphy (Archives 1989;113:1071)
Gross: multiple, bilateral nodules in adrenal cortex, grossly visible (up to 2 cm) or microscopic
Micro: proliferation of spindle cells in capsule, surrounding small nests of cortical cells
Very rare
Case reports: 42 year old woman with incidental tumor (Mod Path 1996;9:1170)
Micro: unencapsulated tumor of small, round, epithelioid cells; mostly hemorrhagic in case above
Positive stains: CD34 (weak)
Adrenocortical carcinoma
Adrenocortical carcinoma-general
Rare, 0.5-2 cases per million annually in US
No gender preference, mean age 50 years, small peak before age 20 years
Associated with Li Fraumeni syndrome, Beckwith-Wiedemann syndrome, congenital adrenal hyperplasia
50% are functional and associated with virilizing and other syndromes; cannot determine function from morphology
Lack of function may be due to deletions in enzymes required for cortisol synthesis
Highly necrotic tumors may cause fever and simulate an infectious process clinically
Tend to invade adrenal vein, vena cava, adjacent kidney, retroperitoneum; may cause thromboemboli
Metastases to liver (60%), regional lymph nodes (40%), lungs (40%), peritoneal and pleural surfaces, bone, skin (anaplastic tumors), retroperitoneum
Only definitive criteria for malignancy are distant metastasis or local invasion
Often cannot differentiate between adenoma and carcinoma-call adrenocortical neoplasm and estimate risk of recurrent or metastatic tumor
In children, malignant appearing tumors often have good prognosis, particularly if < 5 years old at diagnosis, complete resection, tumor < 400g, < 15 mitotic figures/20 HPF, minimal tumor necrosis
Poor prognostic factors: mitotic activity, venous invasion, weight of 50g+; diameter of 6.5 cm+, Ki-67/MIB1 labeling index of 4%+, p53+
Original Weiss criteria for malignancy (AJSP 1984;8:163), modified as indicated below, require 3 or more of these factors:
(1) nuclear grade III or IV based on criteria of Fuhrman
(2) > 5 mitotic figures/50 HPF (40x objective), counting 10 random fields in area of greatest number of mitotic figures on 5 slides with greatest number of mitoses
(3) presence of atypical mitotic figures (abnormal distribution of chromosomes or excessive number of mitotic spindles)
(4) clear or vacuolated cells comprising 25% or less of tumor
(5) diffuse architecture (more than 1/3 of tumor forms patternless sheets of cells; trabecular, cord, columnar, alveolar or nesting is not considered to be diffuse
(6) microscopic necrosis
(7) venous invasion (veins must have smooth muscle in wall; tumor cell clusters or sheets forming polypoid projections into vessel lumen or polypoid tumor thrombi covered by endothelial layer)
(8) sinusoidal invasion (sinusoid is endothelial lined vessel in adrenal gland with little supportive tissue; consider only sinusoids within tumor)
(9) capsular invasion (nests or cords of tumor extending into or through the capsule with a stromal reaction); either incomplete or complete
Note: above criteria may not apply to childhood tumors
Modified Weiss criteria (using 1 if above factor is present in tumor, 0 otherwise):
2x mitotic rate score + 2x clear cytoplasm score + abnormal mitoses + necrosis + capsular invasion (score of 3 or more suggests malignancy, AJSP 2002;26:1612)
Malignant cases compared to adenomas usually show loss of heterozygosity (61%) at some loci; retinoblastoma gene (80%), p53 (44%), 9p (26%), 1p (22%), 3p (22%); more likely to be aneuploid or tetraploid (Hum Path 1998;29:518); spindling of tumor cells also suggests malignancy
2 year survival is 50%, 5 year survival is 20-35%
Treatment: surgical excision; excision of solitary lung metastases
Case reports: coexistent choroid plexus carcinoma in 18 month boy with no family history, both tumors p53+ (Archives 2002;126:70), tumor in MSH2 carrier, but without MSH2 mutation in adrenal tumor (Hum Path 2000;31:1522), small histologically benign tumor (40g) that metastasized after excision (Archives 1986;110:1076)
Gross: unencapsulated; large (200 grams, 20 cm); variegated cut surface due to hemorrhage, cysts, necrosis; often has soft, friable intratumoral nodules; often invasion of major veins
Gross images: (1) large tumor dwarfing kidney; (2) large tumor displacing kidney and spleen; (3) 250g, 10 cm tumor; (4) large tumor compressing kidney #1; #2; #3; (7) large tumor with hemorrhage #1; #2
Micro: various growth patterns; well differentiated to anaplastic cells (giant cells with bizarre hyperchromatic nuclei); capsular invasion, marked mitotic activity with atypical forms; may have neutrophils, tumor giant cells, sarcomatoid features, eosinophilic globular inclusions, necrosis
Cytology: single cells, poorly cohesive cell clusters in necrotic background, often but not always marked nuclear atypia and mitotic activity; cytoplasm is vacuolated to densely eosinophilic
Micro images: (1) polygonal cells with vascular stroma and focal necrosis; (2) tumor cells have abundant eosinophilic cytoplasm, mildly pleomorphic and vesicular nuclei, prominent nucleoli; (3) capsular infiltration; (4) tumor with mitotic figure (arrow); (5) adrenal vein invasion; (6) synaptophysin+; (7) various micro images and stains; (8) A: polygonal cells with abundant eosinophilic and microvacuolar cytoplasm, round and bizarre nuclei; B: p53+; C: p53+ normal appearing adrenal cortex (curved arrows); medulla was p53- (straight arrows); D: EM shows tubular cristae (solid arrows) and cytoplasmic fat (open arrows)
Micro images: A: H&E; B: calretinin+; C: MelanA+; D: inhibin negative
Virtual slides: adrenocortical carcinoma
Positive stains: vimentin, MelanA/MART1 (Archives 2002;126:170, AJSP 1998;22:57), synaptophysin, inhibin (usually, Mod Path 1998;11:1160), bcl2 (Mod Path 1998;11:716), adrenal 4 binding protein (regulates expression of steroid enzymes, Hum Path 1995;26:1154), p53; variable synaptophysin, neurofilament, neuron specific enolase, calretinin, HepPar1, S100 and CAM 5.2
Negative stains: CK7, CK20, EMA, CEA, B72.3, chromogranin
Molecular: usually aneuploid (69%), but ploidy is not helpful in determining behavior
EM: tubular cristae in mitochondria and droplets of cytoplasmic fat; occasionally dense core granules (associated with neuroendocrine immunostains)
EM images: figure 3D
DD: adrenal cortical adenoma (see Weiss criteria above), renal cell carcinoma (usually contains glands which may contain red blood cells, glycogen+, keratin+, EMA+, CD10+, MelanA-, synaptophysin-, inhibin-), adrenal medullary tumors (inhibin-, MelanA-, calretinin-, chromogranin+), hepatocellular carcinoma
References: AJSP 1997;21:556 (MIB1 and p53 as prognostic markers)
Adenosquamous adrenocortical carcinoma
Case report at Archives 1995;119:260
DD: metastases
Carcinosarcoma
Has sarcoma-like elements
Case reports: with osteoid differentiation and hyperaldosteronism (AJSP 1993;17:941), 29 year old woman with virilization (AJSP 1992;16:626)
Clear cell carcinoma
Negative for albumin ISH, which differentiates adrenal tumors metastatic to liver from liver primaries (AJSP 2000;24:177)
Myxoid carcinoma
Rare, <20 cases reported
Presence of myxoid change does not appear to influence tumor behavior
Case reports: myxoid change and extensive lipomatous metaplasia (Archives 2003;127:227), 41 year old woman with coexisting parathyroid hyperplasia and pituitary tumor (Archives 1979;103:635), Archives 1994;118:1151
Micro: atypical round cells with eosinophilic to vacuolated cytoplasm, stroma with copious mucinous material
Positive stains: Alcian blue; usual stains for adrenocortical carcinoma
Negative stains: PAS, mucicarmine
References: AJSP 2000;24:396
Oncocytic carcinoma
Rare, <50 cases reported
Ages 39-71
Usually non-functional
One tumor invaded the inferior vena cava and extended into the right atrium, another metastasized to bone
Weiss system for malignancy not applicable because all tumors have eosinophilic tumor cytoplasm, diffuse architecture and nuclear atypia; better to use criteria of mitotic activity, necrosis, invasion, MIB1 activity
Gross: large yellow-tan tumors (8.5 to 17.0 cm), well demarcated from adjacent kidney; thin rim of normal adrenal gland
Gross image: large multinodular yellow tumor with central necrosis
Micro: diffuse proliferation of polygonal cells with abundant granular and eosinophilic cytoplasm, large nuclei, prominent nucleoli; occasional mononuclear and binucleated giant cells; often extracapsular extension, blood vessel invasion and necrosis; variable atypia; rare mitotic figures
Micro images: (1) large, polygonal, eosinophilic tumor cells; (2) cords of tumor cells separated by dilated sinusoids; (3) cells have abundant eosinophilic cytoplasm and prominent nucleoli; (4) aggregates of foamy cells; (5) AE1/AE3+; (6) inhibin+
Positive stains: AE1-AE3, CAM5.2, inhibin (1 of 4 tumors)
EM: numerous mitochondria
EM images: prominent nucleoli, perinuclear rough endoplasmic reticulum, mitochondria, lipid droplets
DD:
(a) adrenocortical oncocytoma (well circumscribed, no capsular extension, no vascular invasion),
(b) conventional adrenocortical carcinoma,
(c) pheochromocytoma (episodic hypertension, zellballen pattern, chromogranin+, S100+ in sustentacular cells, abundant dense-core membrane-bound granules on EM),
(d) eosinophilic variant of chromophobe renal cell carcinoma (EMA+, microvesicles by EM),
(e) metastatic hepatocellular carcinoma (Hepar-1 positive)
References: Mod Path 2002;15:973
Staging of Adrenocortical carcinoma
Staging system proposed by MacFarlane, modified by Sullivan and Henley
Stage 1: Confined to gland, 5 cm or less
Stage 2: Confined to gland, more than 5 cm
Stage 3: Extends outside gland without involving adjacent organs, any size
Stage 4: Distant metastasis or involvement of adjacent organs
TNM Staging system from AJCC, 7th edition
Note: TNM and stage grouping are for adrenal cortical carcinoma only, and were created for first time in AJCC 7th edition
Classification is not intended for adrenal medullary tumors, adenoma or neuroblastoma
Primary tumor (T)
TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
T1: Tumor 5 cm or less in greatest dimension, no extra-adrenal invasion
T2: Tumor greater than 5 cm, no extra-adrenal invasion
T3: Tumor of any size with local invasion, but not invading adjacent organs*
T4: Tumor of any size with invasion of adjacent organs*
* Adjacent organs are kidney, diaphragm, great vessels, pancreas, spleen and liver
Regional lymph nodes (N)
Note: regional lymph nodes are aortic (para- and peri-aortic) and retroperitoneal NOS
NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Metastasis in regional lymph node(s)
Distant metastasis (M)
M0: No distant metastasis
M1: Distant metastasis
Stage grouping
I - T1 N0 M0
II - T2 N0 M0
III - T1-T2 N1 M0 or T3 N0 M0
IV - M1 or T4 or T3 N1 M0
Features to report-Adrenocortical carcinoma
Tumor size and weight
Tumor location
Histologic type
Invasion of adjacent tissue
Margin involvement
Angiolymphatic invasion
Sinusoidal invasion
Capsular invasion
Presence of tumor necrosis, hyperplasia, adenoma, nuclear grade, mitotic rate, presence of atypical mitotic figures, % clear or vacuolated cells, presence of diffuse architecture, myelolipomatous change
Lymph nodes (number sampled, number with tumor)
Correlation with clinical history, laboratory findings may be helpful
Adrenal medulla
Synthesizes and secretes primarily catecholamines (norepinephrine and epinephrine) in response to signals from preganglionic nerve fibers in sympathetic nervous system
Norepinephrine: local transmitter, chiefly of sympathetic postganglionic neurons
Epinephrine: systemic transmitter, interacts with alpha and beta adrenergic receptors
Tyrosine –1à DOPA –2à Dopamine –3à Norepinephrine –4à Epinephrine
DOPA –5à 3-methoxytyrosine –6à vanillactic acid (VLA)
Dopamine –5,6à homovanillic acid (HVA)
Norepinephrine –5à normetanephrine –6à vanilllylmandelic acid (VMA)
Epinephrine –5à metanephrine –6à vanilllylmandelic acid (VMA)
1: Tyrosine hydroxylase; 2: aromatic L amino acid decarboxylase; 3: dopamine beta-hydroxylase; 4: phenylethanolamine-n-methyl transferase; 5: catechol-o-methyl transferase; 6: monoamine oxidase and aldehyde dehydrogenase
Defined as increase in mass of adrenal medullary cells and expansion into areas of gland not normally present, such as the tail
May cause hypertensive symptoms similar to pheochromocytoma, Cushing’s syndrome
Bilateral; either nodular or diffuse
Familial cases associated with MEN 2a, 2b/3, von Hippel-Lindau disease, neurofibromatosis type 1, familial Beckwith-Wiedemann syndrome
Sporadic cases associated with cystic fibrosis, sudden infant death syndrome, nonfamilial Beckwith-Wiedemann syndrome
Note: nodular hyperplasia in MEN 2a or 2b patients may act similar to pheochromocytomas
(Description of MEN syndromes are under Pheochromocytoma)
Diagnosis: should be based on morphometry (medullary volume > 10% of gland)
Treatment: bilateral adrenalectomy
Gross: familial cases usually have multiple unencapsulated, gray-tan nodules in both glands
Micro: alveolar, trabecular or solid patterns of medullary cells with variable size and shape; often medullary tissue in alar and tail regions of gland
Positive stains: chromogranin, synaptophysin, NSE
EM: resemble normal medullary cells
Molecular: may be monoclonal
DD: cortical atrophy making medulla appear prominent, pheochromocytoma (usually > 1 cm, increased urinary excretion of epinephrine, norepinephrine, VMA and metanephrines)
Adrenal medullary tumors-general
Broadly classified into sympathetic system tumors or adult neuroendocrine tumors
Sympathetic system tumors: neuroblastoma, ganglioneuroblastoma, ganglioneuroma; usually infants/children; occur anywhere along sympathetic chain; must differentiate from Ewing’s sarcoma/PNET
Adult neuroendocrine tumors: pheochromocytoma, adrenal medullary hyperplasia; usually adults or children with genetic syndromes
May arise from sympathetic ganglia or pheochromocytoma
Low grade tumors, may recur locally, only occasionally lead to death
DD: metastases from occult primary in skin, mucous membranes, eyes;
Also called paraganglioma of adrenal medulla (extra-adrenal tumors are called extra-adrenal paragangliomas)
Rare catecholamine secreting tumor (0.005% to 0.1% of unselected autopsies)
Described by Poll in 1905 as having dusky [pheo] color [chromo] of cut surface
Causes surgically correctable hypertension (also aldosterone-secreting tumors, renal artery stenosis)
Represent 0.1% of patients with hypertension, but it may be fatal
Mean age 47 years in one series, range 3-81 years
Called “10% tumor”: 10% bilateral (probably higher), 10% outside adrenal medulla, 10% metastasize (actually is probably much higher), 10% in children
Extra-adrenal tumors secrete only norepinephrine, have 20% malignancy rate
In children, usually extra-adrenal, bilateral, associated with MEN 2a/2b
Metastases usually to lymph nodes, skeletal system (ribs, spine), liver, lung; occasionally to brain, peritoneum, stomach, diaphragm, pleura, spleen, pancreas, ileum, and kidney
Occasionally associated with melanoma (Archives 1998;122:63), also neurofibromatosis, renal artery stenosis due to dysplasia, other paragangliomas, adrenal cortical tumors, von Hippel-Lindau disease
Familial causes of pheochromocytomas:
Probably more than 10% of cases; usually younger age of onset (10-20 years vs. 40-60 years), bilateral (70% vs. 10% in sporadic), multicentric, associated with other neoplasms, male gender
MEN 1: pituitary tumors, parathyroid hyperplasia or adenoma, pancreatic hyperplasia or adenoma, carcinoid tumors
MEN 2a/2: Sipple first described in 1961; autosomal dominant with high penetrance, 30-50% have pheochromocytomas, all have medullary thyroid carcinoma, 10-15% have parathyroid hyperplasia; due to mutation in RET proto-oncogene
MEN 2b/3: MEN2a signs/symptoms plus mucosal neuromas and ganglioneuromas; autosomal dominant or sporadic; may lack parathyroid hyperplasia
Sturge-Weber: cavernous hemangiomas (port-wine spots) of trigeminal nerve (cranial nerve V), pheochromocytomas
von Hippel Lindau: 10-20% of patients; cysts of kidney, liver, epididymis; renal cell carcinomas (clear cell type), pheochromocytomas, angiomas, cerebellar hemangioblastomas
von Recklinghausen (neurofibromatosis type 1): 1-5% of patients; neurofibromatosis, schwannomas, meningiomas, gliomas, pheochromocytomas; composite tumors with neuroblastoma, ganglioneuroma or ganglioneuroblastoma may be associated with neurofibromatosis 1, Mod Path 2002;15:183
Malignant criteria or suggestive features for pheochromocytoma
Most reliable is presence of metastases (lymph nodes, liver, lung, bone)
Malignant cases have MIB-1 positive cell rate of 2-3% or more (Hum Path 1998;29:522; Mod Path 1999;12:1107)
Malignant cases have strong tenascin staining (AJSP 2001;25:1419)
PASS score (Pheochromocytoma of the Adrenal gland Scaled Score)
Reference: AJSP 2002;26:551
Benign if 0-3 points, potential for malignancy if 4+ points; each feature present gets points added
1 point: vascular invasion, capsular invasion, profound nuclear pleomorphism, hyperchromasia
2 points: invasion of periadrenal adipose tissue, large nests or diffuse growth, focal or confluent necrosis, high cellularity, tumor cell spindling, cellular monotony, 4+ mitotic figures per 10 high power fields, atypical mitotic figures
Symptoms: related to catecholamine hypersecretion (usually norepinephrine > epinephrine); usually hypertension (abrupt; with tachycardia, palpitations, headaches, tremor, sense of apprehension, weight loss; unresponsive to treatment; isolated paroxysmal episodes of hypertension in < 50%)
Triad of sweating attacks, tachycardia and headaches is relatively specific for pheochromocytoma
Rarely associated with Cushing’s or other syndromes
Catecholamine cardiomyopathy: myocardial instability, ventricular arrhythmias; due to ischemic damage from vasoconstriction of coronaries or direct toxicity; cardiac biopsy shows myocytolysis, interstitial fibrosis, mononuclear inflammation
Diagnosis: increased urinary excretion of catecholamines or metabolites (vanilllylmandelic acid-VMA or total metanephrines); elevated serum chromogranin A levels
Treatment: surgery after premedication with adrenergic blockers
Case reports: composite tumor with pheochromocytoma, ganglioneuroma, diffuse and nodular medullary hyperplasia in MEN 2a patient (AJSP 1997;21:102); composite tumor with ganglioneuroma and separate renal angiomyolipoma (Archives 1985;109:470), bilateral pheochromocytoma-ganglioneuroma in neurofibromatosis 1 patient (AJSP 1993;17:837), with ganglioneuroma (Hum Path 1988;19:1352), bilateral composite tumors with malignant peripheral nerve sheath tumor and GANT tumors in neurofibromatosis 1 patient (AJSP 1996;20:889), 39 year old woman with composite MPNST and pheochromocytoma (Archives 1988;112:266), pigmented tumors due to neuromelanin (Archives 2004;128:e125, Hum Path 1993;24:420, Mod Path 1993;6:175), recurrent tumor in 18 year old with family history of MEN2a and intracytoplasmic lipid droplets (Archives 1990;114:892); ACTH producing tumors (Archives 1984;108:545, Archives 1977;101:31)
Gross: small and circumscribed to large hemorrhagic and necrotic tumors (1g to 4 kg); mean 7 cm/200 g; small tumors have rim of compressed adrenal gland; lobulated; yellow-red-brown; familial tumors are bilateral and multicentric, and adjacent medulla may appear hyperplastic
Chromaffin reaction: fresh tumor turns dark brown if add potassium dichromate at pH 5-6 (Zenker’s)
Gross images: necrotic and hermorrhagic tumor; tan-red tumor; von Hippel-Lindau patient
Micro: zellballen (small nests or alveolar pattern), trabecular or solid patterns of polygonal/spindle shaped cells in rich vascular network; cells have finely granular basophilic or amphophilic cytoplasm; intracytoplasmic hyaline globules; round/oval nuclei with prominent nucleolus and variable inclusion-like structures; may have marked pleomorphism; capsular and vascular invasion common in benign behaving tumors; nests outlined by sustentacular cells (cannot see in H&E but S100+); amyloid also common (Hum Path1992;23:33); rare/no mitotic figures
Unusual morphological features: coexisting cortical hyperplasia, vacuolar degeneration of tumor cells, presence of pheochromoblasts (small cells), ganglion-like cells, calcospherites, melanin pigmentation, insular growth pattern, brown fat
May be mixed with neuroblastoma, ganglioneuroma, ganglioneuroblastoma, cortical adenoma, spindle cell sarcoma
Micro images: nests of large pink cells with prominent vasculature between nests #1; #2; alveolar pattern; alveolar and trabecular patterns; tumor with delicate vasculature; abundant basophilic cytoplasm; nuclear pseudoinclusions and degenerative atypia; pigmented pheochromocytoma; negative MelanA/A103 staining (right); various images; Ki-67 in benign and malignant paraganglioma
Virtual slides: pheochromocytoma
Positive stains: chromogranin, synaptophysin (also present in adrenal cortical carcinomas), S100 (sustentacular cells), PAS+ diastase resistant hyaline globules, tenascin (strong in clinically malignant tumors), catecholamines, neuron specific enolase, neurofilament, NESP-55 (preliminary study, AJSP 2004;28:1371), variable vimentin, bcl2, focal HMB45 (Archives 1992;116:151)
Negative stains: MelanA/Mart1, inhibin, keratin (usually), calretinin
Molecular: loss of heterozygosity (LOH) of 1p34-36 in 45%, VHL gene (3p25) in 45% (Hum Path 1997;28:411); also genetic changes in syndromes above; also mutations in genes for succinate dehydrogenase
EM: numerous membrane-bound electron dense granules containing catecholamines, tubulolamellar mitochondria, predominantly rough endoplasmic reticulum
EM images: neurosecretory granules #1; #2
DD: (small blue cell tumors): Ewing’s/PNET, small cell osteosarcoma, small cell carcinoma (neuroendocrine carcinoma), rhabdomyosarcoma, PNET/medulloblastoma, monomorphic Wilm’s tumor, neuroblastoma, carcinoid, lymphoma
DD: adrenocortical carcinoma (inhibin+, MelanA+, calretinin+, Mod Path 2003;16:591, free full text)
References: Hum Path 1987;18:909 (staining of composite tumors); Hum Path 1980;11:205 (nuclear inclusions)
Mixed with neuroendocrine carcinoma
Rare, case report at Archives 1999;123:1274
Gross image: well circumscribed mass with variegated cut surface and necrosis
Micro images: neuroendocrine carcinoma-upper left and pheochromocytoma-lower right; neuroendocrine carcinoma in vaginal wall
Oncocytic variant
Rare, case report at AJSP 2000;24:1552
Gross: solid, brown cut surface
Micro: large polygonal tumor cells with eosinophilic granular cytoplasm; arranged in nesting, alveolar, and trabecular patterns
Positive stains: chromogranin, synaptophysin, neuron-specific enolase, neurofilament, serotonin, bombesin, ACTH, vimentin, desmin, S-100, AE1/3, CAM 5.2, CK 7, CK 20
EM: closely packed mitochondria and dense-core membrane-bound granules
Neuroblastic tumors
Second most common solid childhood neoplasm, after CNS tumors
15% of neoplasms in children 4 years and younger
There is a continuum from neuroblastoma (most immature) to ganglioneuroblastoma to ganglioneuroma (most mature)
Have tumor cell differentiation between neuroblastoma and ganglioneuroma
Usually young children but also adults
Common in retroperitoneum or mediastinum (similar to ganglioneuroma) but NOT common in adrenal gland
Better prognosis than neuroblastoma
Virtual slides: ganglioneuroblastoma (not classified)
Nodular variant
Also called composite schwannian stroma rich/stroma dominant and stroma poor neuroblastic tumor, immature
Nodules may represent aggressive tumor clones
Poorer prognosis (unfavorable histology) compared to intermixed variant
Also includes case with primary tumor of ganglioneuroma or ganglioneuroblastoma, intermixed but metastases of neuroblastoma
Gross: hemorrhagic neuroblastoma nodules
Micro: abrupt demarcation of neuroblastic component (stroma poor) from ganglioneuroma (stroma dominant) or ganglioneuroblastoma, intermixed (stroma rich), with pushing borders and variable fibrous pseudocapsule; ganglioneuroma or ganglioneuroblastoma, intermixed component may be at periphery; neuroblastic component may resemble lymphocytes
Intermixed variant
Also called schwannian stroma rich neuroblastic tumor, imperfect
Favorable histology (better prognosis) compared to nodular variant of ganglioneuroblastoma
Gross: no distinct hemorrhagic nodule
Micro: random intermingling (i.e. infiltrative interface) of neuroblastic nests and ganglioneuromatous component; neuroblasts may have variable differentiation; usually abundant neuropil; ganglioneuroma / ganglioneuroblastoma component is > 50% of volume)
DD: differentiating neuroblastoma (similar, neuroblastomas have >5% ganglion cells but 50% or less ganglioneuroma / ganglioneuroblastoma component)
Also called schwannian stroma dominant neuroblastic tumor
Divided into maturing (also called stroma rich well differentiated neuroblastic tumor) and mature subtypes
Benign, fully differentiated neuroblastoma
Patients older than neuroblastoma
Most common neoplasm of sympathetic nervous system in adults
Usually in retroperitoneum or mediastinum (similar to ganglioneuroblastoma); less than 30% in adrenal gland
May be associated with neuroblastoma or pheochromocytoma
Often elevated serum VMA, HVA
Often severe diarrhea due to VIP secretion
Treatment: excision of ganglioneuroma mature subtype is curative, although it rarely transforms to MPNST
Gross: large, sharply circumscribed, firm with homogenous gray-white cut surface; must sample thoroughly to rule out neuroblastic differentiation (areas of different color or consistency)
Gross images: (1) well-circumscribed multinodular tumor; (2) well circumscribed gray-white tumor #1; #2; #3
Micro: resembles neurofibroma plus numerous clusters of mature ganglion cells, often multinucleated; Schwann cell component may resemble MPNST; either mature (every ganglion cell is mature, no neuroblastomatous component although may be lymphocytes) or maturing (minor component of differentiating neuroblasts or maturing ganglion cells, but no distinct nests of neuroblastomatous stroma)
Micro images: (1) clusters of ganglion cells in a neurofibroma-like background #1; #2; (3) rare case with Leydig cells; (4) ganglion cells are S100+
contributed by Professor D. Y. Cohen, Herzliyah Medical Center, Israel - retroperitoneal tumor - #1; #2; #3; #4; #5; #6
EM: resemble sympathetic ganglion cells
DD: gangioneuroblastoma
Also called schwannian stroma-poor neuroblastic tumor
#4 most common malignancy (solid or not) in children after leukemia, medulloblastoma/PNET, astrocytoma; rare in adults
500 new cases/year in US
Most common tumor before age 1 year; 80% are under age 4 years, median age at diagnosis is 21 months
Causes 15% of childhood cancer deaths
Screening programs detect more tumors, but don’t reduce mortality (Int J Cancer 2003;103:538)
Derived from neural crest cells capable of multilineage differentiation
25% occur in adrenal medulla, also along sympathetic chain (neck, posterior mediastinum, paravertebral, retroperitoneum)
Associated with Beckwith-Wiedemann syndrome, Hirschsprung’s disease, neurofibromatosis type 1, fetal hydantoin syndrome, opsoclonus/myoclonus, heterochromia iridis, Cushing’s syndrome
Maturation: 30% regress or mature to ganglioneuroma; maturation associated with high numbers of Schwann cells that migrate into tumor, express high levels of NGF receptors p140 TrkA and p75 NGFR, and induce differentiation
For children age 1+, some neuroblastomas make trophic factor for Schwann cells, leading to inward migration of Schwann cells, leading to TrkA expression, leading to tumor cell differentiation
For children less than age 1, neuroblastomas don't make trophic factor for Schwann cells, causing apoptosis
May also differentiate into ganglioneuroblastoma
Clinical: young children present with large abdominal masses that may fill abdomen or thorax, fever, weight loss; usually increased levels of catecholamines, but without symptoms
Usually adrenal, but 1/3 in head and neck, mediastinum or pelvic area
Older children may present with bone pain, respiratory or GI complaints due to metastatic disease
Spreads to adjacent tissue including kidney, spine (dumbbell extension)
Metastases are usually early and widespread to bone marrow, bones (skull or orbit; multiple, often symmetrical), lymph nodes, meninges, liver (Pepper’s syndrome), ovary, paratesticular region; lung and brain uncommon
High urinary catecholamines
Survival: 3 year overall survival is 30%
5 year survival (data several years old): age < 1 year old and stage I/II: 95-98%; <1 year old and stage IV-S: 80%
<1 year old and stage IV: > 50%; > 1 year old and stage III/IV: 10%
Treatment: surgery, chemotherapy, bone marrow transplantation
Case reports: metastatic disease with pheochromocytoma differentiation after surgery and chemoradiotherapy (AJSP 2004;28:548), presentation as primary ovarian tumor (AJSP 1982;6:283, patient #5), association with anencephaly (Archives 1979;103:119)
Gross: varies from in situ lesions (minute nodules) to 1 kg; usually well circumscribed but may be infiltrative; composed of soft, gray-pink, brain-like tissue; well differentiated tumors are yellow-tan and resemble ganglioneuroma; large tumors have hemorrhage, necrosis, calcification, cysts; 90% unilateral; may be locally invasive to liver or pancreas
Gross images: (1) right sided neuroblastoma displacing liver; (2) encapsulated tumor; (3) pink-gray tumor; (4) necrotic and hemorrhagic tumor; (5) post-chemotherapy
Micro: vaguely nodular due to incomplete fibrous encapsulation; small blue cell tumor (minimal cytoplasm, hyperchromatic round nuclei), with poorly defined cytoplasmic borders; 25-35% have Homer-Wright pseudorosettes (tumor cells surround central space filled with fibrillar extensions [neurites] of cells without a central lumen); may have neuropil (fine fibrillary matrix) between tumor cells; may have alveolar, pseudovascular or Schiller-Duvall body appearance due to hemorrhage; may have prominent calcification; necrosis common; rarely has “zellballen” appearance or bizarre tumor giant cells
INPC classification of neuroblastoma:
Classic (undifferentiated) neuroblastoma: also called grade III/IV or stroma-poor; small/medium cells with thin rim of cytoplasm, indistinct cell borders, round/oval nuclei with salt and pepper (coarsely granular) chromatin, indistinct nucleoli; no neuropil, although coagulative necrosis may resemble neuropil; 5% or less of tumor has features of differentiation towards ganglion cells with vesicular nuclei and prominent nucleoli; no/minimal ganglioneuromatous stroma
Poorly differentiated neuroblastoma: classic pattern but with neuropil
Differentiating neuroblastoma: 6-49% of tumor cells show ganglionic differentiation (abundant eosinophilic or amphophilic cytoplasm, large eccentric nuclei with vesicular chromatin and single prominent nucleoli), often at periphery of tumor; if 50% or more, call ganglioneuroblastoma, intermixed); usually abundant neuropil
Mitotic karyorrhexis index: number of karyorrhectic cells based on 5000 cell counts in random fields; either low (<100), intermediate (100-200) or high (>200)
Note: diagnosis of “neuroblastic tumor unclassifiable” may be appropriate for small biopsies; “neuroblastoma, NOS” may be appropriate if poor histologic sections, hemorrhage, necrosis, crush, cystic degeneration or marked calcification
Micro images: low power; undifferentiated neuroblastoma; various images
Virtual slides: neuroblastoma
Positive stains: chromogranin, synaptophysin, vimentin, neurofilament, neuron-specific enolase (monoclonal antibody is more specific), nerve growth factor receptors, ALK
Negative stains: p53, CD99, FLI1, desmin, myogenin, keratin, CD45, variable EMA, variable WT1
Molecular: 1p36.33 deletion, N-myc amplification, 14p deletion, 17q gain, diploid or hyperdiploid, TrKA gene expression abnormalities
EM: neurosecretory granules, synaptic endings, neurites forming complex interdigitating meshwork in center of Homer-Wright pseudorosettes, neuropil represents mass of unmyelinated axons
EM images: neurosecretory granules
DD: rhabdomyosarcoma (strap cells, rhabdomyoblasts, muscle marker+), Ewing’s/PNET (usually does not present with metastatic disease, older children, no neuropil, CD99+, chromogranin-), lymphoma, desmoplastic small round cell tumor, monophasic Wilm’s tumor (none have differentiation towards immature ganglion cells)
Neuroblastoma in situ
Usually incidental finding at autopsy in 0.4 to 2.5% of infants less than 3 months
May not be neoplastic or may mature into ganglioneuroma
Micro: clusters of immature neuroblasts from 0.7 to 9.5 mm, with frequent cystic change
Treatment effect
Cannot grade tumors as favorable or unfavorable
Micro: extensive fibrosis and calcification may obscure margin involvement; also necrosis and chronic inflammation
Staging of neuroblastic tumors
Evans staging of neuroblastomas
I - tumor confined to structure or organ of origin
II - tumor extends in continuity beyond structure or organ of origin, doesn't cross midline, variable ipsilateral nodal metastases
III - tumor extends in continuity beyond midline; variable bilateral nodal metastases
IV - tumor metastatic to viscera, distal lymph nodes, soft tissue, skeleton
IV-S (special) - stage I or II with remote disease in liver, skin, bone marrow (with no bony destruction)
Stage IV-S (4S): small/undetectable primaries with disease involving liver, skin or bone marrow; survival of 60-90%; median age 4 months, primary usually adrenal (also retroperitoneum, mediastinum); usually have favorable histology; patients dying of progressive disease have either unfavorable histology or N-myc amplification (Hum Path 1996;27:1135)
Ten year survival by Evan’s stage: I-88%, II-90%, III-63%; IV-21%, IVs-81%
International neuroblastoma staging system (INSS)
1 - localized tumor with complete gross (not necessarily microscopic) excision, negative representative ipsilateral lymph nodes microscopically; note: nodes removed with primary tumor may be positive; includes grossly resectable tumor in midline from pelvic ganglia or organ of Zuckerkandl
2A - localized tumor with incomplete gross excision, negative representative non-adherent ipsilateral lymph nodes microscopically; note: includes midline tumor that extends beyond one side of vertebral column and is unresectable
2B - localized tumor with positive representative non-adherent ipsilateral lymph nodes; enlarged contralateral lymph nodes must be negative microscopically; note: includes midline tumor that extends beyond one side of vertebral column, is unresectable with positive ipsilateral lymph node involvement (on side of extension); also includes a thoracic tumor with malignant unilateral pleural effusion
3 - unresectable unilateral tumor infiltrating across midline or localized unilateral tumor with contralateral regional lymph node involvement; note: includes midline tumor with bilateral extension by infiltration (unresectable) or by lymph node involvement; includes a tumor of any size with malignant ascites or peritoneal implants
4 - any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin or other organs (except 4S)
4S - localized primary tumor (stage 1, 2A or 2B) with dissemination limited to skin, liver or bone marrow (limited to infants < 1 year of age); note: marrow involvement should be minimal (<10% of total nucleated cell identified as malignant); more extensive involvement should be classified as stage 4
Note: for infants < 1 year, stages 1, 2A, 2B, 3 and 4S have similar rates of 4 year overall survival (98.5%) compared to stage 4 (73%
Prognostic factors for neuroblastic tumors
Poor prognostic indicators: 1p36.33 deletion (subtelomeric region, may be site of differentiation associated genes); N-myc amplification (>10 copies, is associated with 1p36 deletion), 14p deletion, diploidy, low expression of TrkA gene (maturation factor), undifferentiated morphology, high mitotic rate-karyorrhexis index and age 1 year old or more; this group has a 5% cure rate; also 17q+, elevated serum ferritin (> 150 ng/mL)
Note: the more copies of N-myc, the greater the number of double minutes and homogenously staining regions, and the worse the prognosis
Favorable prognostic indicators: age < 1 year regardless of stage, hyperdiploid / near-triploid, high levels of TrkA gene (associated with lack of N-myc amplification), stages 1, 2 or 4S versus stages 3 or 4
Intermediate prognostic indicators: near-diploid/tetraploid, no N-myc amplification, no 1p deletions, low levels of TrkA; older patients; this group has a 25-50% cure rate
Shimada classification:
Features include age, degree of neuroblast differentiation, presence or absence of Schwannian stromal development (stroma-rich or stroma-poor), mitosis-karyorrhexis index (MKI), nodular pattern
Stroma rich: significant number of Schwann cells in association with neuroblastoma cells-corresponds to ganglioneuroblastoma
Stroma poor: undifferentiated or differentiated neuroblastoma
Mitosis-karyorrhexis index (MKI): count of cells undergoing mitosis or karyorrhexis, based on count of 5000 cells; either low (<100 cells), intermediate (100-199 cells) or high (200 or more cells)
Note: the unfavorable histologic features are reported inconsistently by various sources
Favorable histology group:
(a) patients of any age with stroma-rich tumors without a nodular pattern
(b) patients younger than 18 months, with stroma-poor tumors, an MKI less than 200/5000 (200 karyorrhectic cells per 5000 cells scanned) or
(c) patients 18-60 months with stroma-poor tumors, an MKI less than 100/5000, and well-differentiated tumor cells
Unfavorable histology group:
(a) patients of any age with stroma-rich tumors and a nodular pattern
(b) patients of any age with stroma-poor tumors and an MKI more than 200/5000
(c) patients 18-60 months with stroma-poor tumors, differentiated neuroblasts, and an MKI of 100-200/5000
(d) patients 18-60 months with stroma-poor tumors, undifferentiated neuroblasts
(e) patients older than 60 months with stroma-poor tumors
Joshi classification of neuroblastoma:
Grade 1: <10 MF/10 HPF and calcification - good prognosis (5 year survival of 89%)
Grade 2: < 10 MF/10 HPF or calcification, but not both - intermediate prognosis (5 year survival of 77%)
Grade 3: >10 MF/10 HPF and no calcification, any age - poor prognosis (5 year survival of 33%)
International Neuroblastoma Pathology Committee (INPC)
Four major categories: (1) neuroblastoma (schwannian stroma-poor neuroblastic tumor), (2) ganglioneuroblastoma, nodular (composite schwannian stroma-rich/stroma dominant and stroma-poor neuroblastic tumor), (3) ganglioneuroblastoma, intermixed (schwannian stroma-rich neuroblastic tumor), (4) ganglioneuroma (schwannian stroma-dominant neuroblastic tumor)
Favorable histology categories for neuroblastoma include: poorly differentiated, low or intermediate MKI, age < 1.5 years; or differentiating, low MKI, age 5 years or less; or differentiating, intermediate MKI, age < 1.5 years
All other neuroblastomas are unfavorable histology
Overall 5 year survival was 97.8% for favorable versus 35.6% for unfavorable histology groups for neuroblastoma
Ganglioneuroblastoma-intermixed and ganglioneuroma were considered to have favorable histology, and had 100% overall 5 year survival
Ganglioneuroblastoma-nodular was considered to have unfavorable histology, and had 59% overall 5 year survival
Grossing possible neuroblastic tumors
Presence of absence of capsule
Resection margins
Include all heterogeneous areas and interface between them
Cytogenetics
Molecular genetics
EM
Other adrenal malignancies
Very rare
6-10 cm
Spindled or epithelioid
Case reports: 54 year old man (Archives 1988;112:1163)
Positive stains: factor VIII related antigen, CD34
Epithelioid angiosarcomas
Rare
Median age 60 years, range 45-85 years; no gender preference
Aggressive, with death common due to lung metastases
Treatment: excision, chemotherapy
Case reports: epithelioid angiosarcoma (Archives 1999;123:157)
Gross: 6-10 cm; may be cystic-solid
Micro: sheets or nests of epithelioid cells between dilated anastomotic vascular spaces lined by similar cells; tumor cells have intracytoplasmic vacuoles occasionally containing red blood cells
Positive stains: Factor VIII related antigen, CD31, CD34, Ulex europaeus, keratin, B72.3
EM: rod-shaped microtubulated bodies, intracytoplasmic lumen
DD: hemorrhagic infarction of adrenal adenoma with atypical fibroblasts
References: AJSP 1994;18:62
Case report of adrenal tumor in 11 year old Japanese boy (Hum Path 2001;32:1012); patient died 15 months after presentation despite aggressive treatment
Micro: monotonous primitive round cells resembling neuroblastoma
Positive stains: CD99/MIC2
Molecular: t(11;22)(q24;q12) and EWS-FLI1 gene fusion product
DD: neuroblastoma (MIC2/CD99 negative, no Ewing’s/PNET translocation)
Associated with Epstein-Barr virus infection in HIV+ patients (Archives 1997;121:834)
May arise from smooth muscle wall of central adrenal vein
Case reports: 49 year old man with 11 cm tumor, necrosis and prominent mitotic figures (AJSP 1991;15:899), 30 year old HIV+ man (Archives 1995;119:1164), 63 year old man with pleomorphic leiomyosarcoma (Archives 2003;127:e32)
Micro images: pleomorphic leiomyosarcoma - 1: multinodular mass adjacent to kidney; 2: tumor invades liver; 3: pleomorphic tumor cells; 4: bizarre tumor cells and abnormal mitotic figures; 5: desmin+; 6: calponin+
Primary adrenal lymphoma
Rare, <100 cases reported
Usually present with bilateral adrenal masses, often with adrenal hypofunction
Usually diffuse large B-cell lymphomas
Case reports: cytokeratin+, CD45 negative, diffuse large B cell lymphoma (Archives 2001;125:1104), primary diffuse large B cell lymphoma (Archives 1990;114:883), bilateral angiotropic large cell lymphoma (Archives 1991;115:1039), bilateral T cell lymphoma causing adrenal insufficiency (Hum Path 1986;17:634)
Micro images: diffuse large B cell lymphoma
Secondary adrenal lymphoma
Adrenal involvement occurs at autopsy in up to 25% with disseminated lymphoma
Usually no associated adrenal insufficiency
Common at autopsy, usually bilateral
Most common primary sites are breast or lung; also melanoma, renal cell carcinoma, GI tract, thyroid, contralateral adrenal gland
Usually does not affect adrenal function; may cause adrenal insufficiency if extensive (replacing 80%+ of adrenal gland)
Gross: single or multiple firm masses replacing some or all of adrenal gland; hemorrhage and necrosis in larger metastases; tumors are tan-brown to black
Gross images: unknown metastases
DD: adrenal cortical carcinoma (melanA+, inhibin+, calretinin+, synaptophysin+, keratin-, EMA-, metastases are usually opposite)
Very rare in adrenal gland, with < 5 cases reported
Must exclude myeloma (negative bone marrow biopsy, no hypercalcemia, anemia or renal insufficiency)
Case report of adrenal gland tumor (Archives 2004;128:e86)
Paraganglia
Neural crest origin
Paraganglion system is formed by neuroepithelial chief cells scattered throughout the body in 3 chains (branchiomeric, intravagal, aorticosympathetic), associated with the sympathetic [epinephrine secreting] or parasympathetic [norepinephrine secreting] nervous system; also present in viscera
Sympathetic paraganglia are paravertebral and paraaortic; parasympathetic are in head and neck
Terminology based on site of origin, not secretory products
Chief cells are arranged in well-defined nests (zellballen) surrounded by rim of sustentacular cells
Chief cells have cytoplasmic neurosecretory granules containing catecholamines; cannot determine function of cells by their appearance
Are called chromaffin cells because they stain yellow-brown with chromium salts
Adrenal medulla is considered part of paraganglion system
Positive stains: chief cells - synaptophysin and chromogranin; sustentacular cells - S100
Branchiomeric chain: associated with parasympathetic nervous system, along jugular vein, vagus, larynx
Intravagal chain: associated with parasympathetic nervous system; distributed along vagus nerve
Aorticosympathetic chain: associated with sympathetic nervous system; along abdominal aorta
Organ of Zuckerkandl: between renal artery and aortic bifurcation, part of aorticosympathetic group; first described by Emil Zuckerkandl in 1901 (University of Vienna); may maintain blood pressure in early fetal life, involutes after 8th month of gestation
Visceral paraganglia: within bladder, other organs
Carotid body paraganglia: part of branchiomeric system; small ovoid structure on medial side of carotid bifurcation bilaterally; mean total weight is 12 mg; chemoreceptors that respond to changes in arterial O2, CO2 and pH
Glomus coccygeum: also called Luschka’s gland; small (2.5 mm), ovoid vascular structure near tip of coccyx; composed of epithelioid cells in layers around vascular channels; no known function
Micro drawings: carotid bodies; glomus coccygeum
Hyperplasia is most commonly seen in carotid bodies, and is associated with high altitude, chronic obstructive pulmonary disease, systemic hypertension, cystic fibrosis, cyanotic congenital heart disease
May also affect vagal and aorticopulmonary paraganglia
High altitudes are also associated with carotid body paraganglioma
Mechanism is presumably due to chronic hypoxemia
Gross: weight over 30g, diameter > 5 mm
Micro: increased number of lobules, some confluent, composed of increased numbers of sustentacular cells and chief cells with hyperchromatic and mildly enlarged nuclei
DD: paraganglioma (usually > 300 mg, have higher density of chief cells)
Tumors of paraganglia, regardless of location, although paraganglioma of adrenal medulla is termed pheochromocytoma
5-10% occur outside adrenal gland
Associated with von Hippel-Lindau disease, MEN syndromes, Carney’s syndrome, neurofibromatosis type 1
20% are multiple versus 10% for sporadic pheochromocytomas
10-40% are malignant, may recur or metastasize to regional lymph nodes, bone, liver, lung; may cause death
May have cardiovascular symptoms due to toxic effect of norepinephrine on myocardium
Chemodectoma: carotid and aortic body tumor (tumors of paraganglia with a chemoreceptor function)
Familial cases: autosomal dominant with paternal imprinting, linkage to 11q23 and 11q13, usually carotid body paragangliomas, also other sites
Sympathoadrenal paragangliomas are associated with MEN 2a and 2b
Poor prognostic features (malignant behavior): Organ of Zuckerkandl (22%-50% vs. 10%+ in adrenal gland), high mitotic activity; possibly necrosis and vascular invasion; only definitive criteria for malignancy is presence of tumor at site where no normal paraganglionic tissue exists
Case reports: mesenteric paraganglioma (Archives 2002;126:362), organ of Zuckerkandl (Archives 2001;125:1387), retroperitoneal tumor with liver metastases 23 years after resection (Archives 1985;109:373)
Gross: rubbery, firm, may have pseudocapsule, but adherent to adjacent vessels; brown cut surface; variable central scar
Gross images: retroperitoneal tumor #1; #2
Micro: same as pheochromocytoma; nesting (zellballen) or trabecular pattern of cells within a prominent vascular network; zellballen pattern may be obscured by anastomosing bands; nests composed of round/oval cells and giant multinucleated cells with abundant granular eosinophilic or basophilic cytoplasm, may have nuclear atypia and vascular invasion (don’t indicate malignancy); dysmorphic vessels, melanin-like pigment, abundant stroma, osseous metaplasia; intracytoplasmic hyaline globules are present in sympathoadrenal paragangliomas; no mitotic figures except in obviously malignant tumors; no rosettes or acini; usually no chronic inflammatory infiltrate, no necrosis (unless preoperative tumor embolization)
Cytology: irregular clusters of tumor cells with eosinophilic, finely granular cytoplasm and mildly irregular nuclei; may have marked atypia; fine needle aspiration not recommended for carotid body paragangliomas due to high likelihood of misinterpretation and risk for catecholamine crisis and hemorrhage
Micro images: (1) various images of retroperitoneal primary and metastases to stomach and lymph node; (2) encapsulated mass with zellballen pattern #1; #2
Micro images: Ki-67 in benign pheochromocytoma (top) and malignant paraganglioma (bottom)
Stains: same as pheochromocytoma; reticulin highlights nesting pattern; cauda equina tumors are usually keratin negative
Molecular: LOH of 3p21 in 50% in small study (Hum Path 1997;28:411)
EM: chief cells have abundant cytoplasmic neurosecretory granules; may have giant mitochondria with paracrystalline inclusions; sustentacular cells wrap around chief cells and lack neurosecretory granules; no desmosomes
DD: alveolar soft parts sarcoma, MFH, alveolar rhabdomyosarcoma, liposarcoma, melanoma, metastatic carcinoma of kidney, thyroid, adrenal medulla and liver; carcinoid tumors, pancreatic endocrine neoplasms
Aorticopulmonary paraganglioma
Usually arise from paraganglia near base of heart or above aortic arch
May cause hoarseness, dysphagia, chest pain/discomfort; rarely hemoptysis or superior vena cava syndrome
May directly involve pericardium or heart
Case reports: 41 year old man with nonfunctioning mediastinal tumor discovered incidentally (Archives 1992;116:1085)
Gross: large, mean 7.5 cm (range 1-17 cm)
Carotid body paraganglioma
Most common site of extra-adrenal paragangliomas
Present at angle of mandible / bifurcation of common carotid artery as slow growing painless mass
May represent hyperplasia due to hypoxia, particularly at high altitudes
Also associated with hepatic cirrhosis, Carney’s triad (epithelioid leiomyosarcoma, pulmonary chondroma, functioning extra-adrenal paragangliomas)
May cause cranial nerve palsy, dysphagia or carotid sinus syndrome (bradycardia and syncope)
Rarely produces catecholamines
Mean age 40’s
90% benign, 90-95% solitary
May invade locally or spread to lymph nodes or lung (must rule out multicentric tumor)
Adherent to carotid bifurcation, but this does not represent malignant infiltration
May be familial (Archives 1990;114:1272)
Case reports: lung metastases in patient with von Hippel-Lindau disease (Archives 1982;106:235)
Treatment: excision
Gross: mean 4 cm, range 2-8.5 cm
References: functional tumors (Archives 1982;106:599)
Cauda equina paraganglioma
Rare; may attach to filum terminale or caudal nerve roots
Age 30’s to 60’s
Case reports: tumor with ependymal and paraganglionic differentiation (Hum Path 1992;23:835)
Gross: usually intradural, extramedullary, encapsulated
Micro: may have neuronal or ganglionic differentiation similar to ganglionic paraganglioma or composite paraganglioma
Positive stains: NSE, neurofilament; S100 for sustentacular cells
DD: ependymoma
Jugulotympanic paraganglioma
Previously called glomus jugulare tumors
Usually arise lateral in temporal bone (glomus tympanicum tumor) or jugular bulb (glomus jugulare tumor), erode through floor and present as mass of external auditory canal or middle ear; also mass at base of skull, middle ear “polyps”
40% extend into cranial cavity
Usually adults, almost always women
Similar morphology as other paragangliomas, but often removed in small fragments
Often misidentified as hemangiomas due to fragmented specimens
Malignant cases often involve bone
Treatment: surgery, external beam radiation therapy
Case reports: metastatic tumor (Archives 1990;114:976)
Laryngeal paraganglioma
Rare; usually arise from superior paraganglia
Mean age 47 years
Hoarseness and dysphagia
25% mortality; often tender subcutaneous metastases
Gross: 2-5 cm
EM: neurosecretory granules
DD: atypical carcinoid tumor
References: AJSP 1979;3:85
Mediastinal paraganglioma
Usually in anterosuperior mediastinum near aortic arch; also in costovertebral sulcus
Aggressive behavior with substantial morbidity or death in 45% in one study
Organ of Zuckerkandl paraganglioma
Close to normal location of this structure, near anterior wall of aorta and origin of inferior mesenteric artery
May invade inferior vena cava
Micro: often nuclear pseudoinclusions (invagination of cell cytoplasm)
Pigmented paraganglioma
Rare
Case report of incidental retroperitoneal tumor in 57 year old woman (AJSP 1998;22:265)
Gross: jet-black or no gross evidence of pigmentation
Micro: pigment consistent with neuromelanin, a waste product of catecholamine metabolism
EM: dense core neurosecretory granules, usually melanosomes or premelanosomes; case report above had abundant large pleomorphic electron dense granules consistent with lipofuscin or neuromelanin
DD: melanoma
Vagal paraganglioma
Usually women in 30’s and 40’s
Near neck, jugular foramen with extension to base of skull
May cause deviation of palatine tonsil or vagus nerve palsy with hoarseness and dysphagia
Gross: usually well circumscribed, but may invade locally; mean 4 cm, range 2-6 cm
Micro: often prominent hyalinized fibrous septa
Paragangliomas – features to report
Excludes pheochromocytomas
Site of origin
Bilateral or not
Familial or sporadic (based on clinical history)
Tumor size / weight
Histologic type, with brief reference to clinical or endocrinologic data
Composite features (ganglioneuroma, MPNST, other)
Extent of tumor necrosis
Extent of mitotic activity
Other prognostic features (invasion of adjacent tissue, angiolymphatic invasion)
Surgical margins
Other features
Regional lymph nodes (# involved/# inspected)
References: Hum Path 2003;34:112
End of Adrenal Gland chapter