Adrenal Cortex

Slide 1 · Adrenal Cortex

Structure, hormone physiology, hyperfunction, insufficiency, and neoplasia

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Map the cortical zones to their predominant steroid hormones.

Explain hormone excess and deficiency through feedback physiology.

Distinguish causes, morphology, and clinical patterns of major cortical disorders.

Interpret adrenal lesions using morphology, hormone activity, and clinical context.

Slide 3 · The adrenal gland houses two endocrine systems

The cortex and medulla differ in developmental origin, organization, and secretory products.

Cortical cells synthesize steroid hormones; Medullary chromaffin cells release catecholamines.

Cortical pathology may cause excess hormone production, hormone failure, or a mass lesion.

The cortex is the focus of this lecture; Medullary neoplasms form a separate topic.

Slide 4 · Normal adrenal cortex: Zonal organization

Capsule

Fibrous covering

Zona glomerulosa

Aldosterone

Zona fasciculata

Predominant cortical volume; Cortisol

Zona reticularis

Androgens; Some glucocorticoids

Medulla

Catecholamines

Schematic orientation from capsular surface toward the adrenal medulla

Slide 5 · Adrenal zones and predominant outputs

Cortical zone

Principal hormones

Key regulatory linkage

Glomerulosa

Mineralocorticoids (aldosterone)

Renin–angiotensin and potassium

Fasciculata

Glucocorticoids (cortisol)

Pituitary corticotropin (ACTH)

Reticularis

Adrenal androgens; some cortisol

Predominantly corticotropin (ACTH)

Slide 6 · Architecture predicts cortical responses to injury

The zona fasciculata is the broadest zone, comprising roughly three quarters of the cortex.

Glomerulosa lies beneath the capsule; Reticularis borders the medulla.

Chronic corticotropin drive produces enlargement of ACTH-responsive cortical compartments.

ACTH suppression preferentially atrophies fasciculata and reticularis while sparing glomerulosa.

Slide 7 · The hypothalamic–pituitary–adrenal axis

Hypothalamic CRH

Pituitary ACTH

Adrenal cortical cortisol

Glucocorticoid output rises in response to corticotropin.

Cortisol feedback suppresses hypothalamic and pituitary stimulation.

Failure or escape at different levels changes both ACTH and adrenal morphology.

Slide 8 · Feedback explains adrenal atrophy and hyperplasia

High exogenous cortisol

Suppressed pituitary ACTH

Bilateral cortical atrophy

Glucocorticoid medication may suppress endogenous ACTH.

Without trophic ACTH, fasciculata and reticularis regress.

Conversely, sustained ACTH excess drives bilateral cortical hyperplasia.

Slide 9 · Three steroid systems: Principal effects

Steroid class

Major physiologic roles

Characteristic excess

Glucocorticoids

Metabolism; immune suppression; stress response

Cushing syndrome

Mineralocorticoids

Renal Na⁺ retention and K⁺ excretion

Hyperaldosteronism

Adrenal androgens

Sex-steroid precursor contribution

Virilizing syndromes

Slide 10 · A useful first division: Function versus lesion

Hyperfunction: Cortisol, aldosterone, or androgen excess dominates the phenotype.

Hypofunction: Cortical hormone deficiency can be primary or secondary.

Structural pathology: Diffuse or nodular hyperplasia, adenoma, carcinoma, hemorrhage, or infiltration.

The appearance of a cortical mass alone does not establish its hormonal functionality.

Slide 11 · Hormone pattern guides the diagnostic question

Dominant abnormality

Clinical cue

Pathologic question

Cortisol excess

Central adiposity, catabolism, hyperglycemia

ACTH dependent or independent?

Aldosterone excess

Hypertension ± hypokalemia

Autonomous adrenal or renin driven?

Androgen excess

Virilization or precocious puberty

CAH or cortical neoplasm?

Cortisol deficiency

Weakness, hypotension, crisis

Primary adrenal or pituitary?

Slide 12 · Cushing syndrome means sustained glucocorticoid excess

Exogenous glucocorticoid administration is the most common overall cause.

Endogenous hypercortisolism arises from ACTH-dependent or ACTH-independent mechanisms.

Cushing disease specifically denotes pituitary ACTH-producing tumor-associated Cushing syndrome.

The adrenal morphology varies with the source of cortisol excess.

Slide 13 · Classifying endogenous Cushing syndrome

Endogenous cortisol excess

Measure plasma ACTH

ACTH dependent / independent

ACTH-dependent causes include pituitary tumors and ectopic ACTH secretion.

ACTH-independent causes include cortisol-producing adrenal lesions.

The classification predicts whether both glands are stimulated or ACTH is suppressed.

Slide 14 · Pituitary Cushing disease: Causal sequence

Pituitary corticotroph tumor

Excess ACTH

Bilateral adrenal hyperplasia

Excess cortisol

Sustained ACTH stimulation expands steroid-producing cortical cells.

The adrenal glands are effectors, not the autonomous source of the signal.

A corticotroph neoplasm may be small despite substantial systemic consequences.

Slide 15 · Ectopic ACTH: Endocrine effects of nonpituitary tumors

Certain neuroendocrine cancers secrete ACTH outside the pituitary.

Small-cell carcinoma of the lung is a prominent example.

Ectopic CRH secretion can also stimulate pituitary ACTH in rare settings.

High ACTH can produce bilateral adrenal cortical hyperplasia and hypercortisolism.

Slide 16 · Autonomous adrenal cortisol: Suppressed ACTH

Cortisol-secreting adrenal lesion

Elevated circulating cortisol

Feedback inhibition of ACTH

Atrophy of uninvolved cortex

An adenoma, carcinoma, or primary bilateral hyperplasia may produce ACTH-independent cortisol excess.

Both adjacent and contralateral normal cortex can atrophy in unilateral cortisol-secreting tumors.

Slide 17 · Bilateral macronodular adrenal hyperplasia

Primary bilateral macronodular hyperplasia is usually ACTH independent.

Macroscopic nodules are generally greater than 10 mm and can replace much of the cortex.

Some familial and apparently sporadic cases involve germline ARMC5 alterations.

Aberrant hormone receptors can drive cortisol secretion independently of pituitary ACTH.

Slide 18 · Pigmented micronodules and Carney complex

Micronodular cortical lesions are typically below 10 mm and may appear darkly pigmented.

Pigment corresponds to intracytoplasmic lipofuscin in compact cortical cells.

Primary pigmented nodular disease may be sporadic or part of Carney complex.

PRKAR1A pathway defects promote inappropriate cAMP-dependent signaling.

Slide 19 · Cortisol effects explain the clinical phenotype

Cortisol excess

Protein / collagen catabolism

Muscle and skin atrophy

Glucocorticoids also favor hepatic glucose production and impair peripheral glucose uptake.

The net phenotype combines fat redistribution, hypertension, hyperglycemia, and tissue fragility.

Slide 20 · Cushing syndrome: Change in body composition

Truncal obesity develops with rounded facial contours (“moon facies”).

Fat may accumulate in the posterior neck and upper back.

Muscle mass falls because glucocorticoids promote protein catabolism.

Proximal weakness reflects preferential atrophy of type II myofibers.

Slide 21 · Cushing syndrome: Skin and skeletal pathology

Collagen loss produces thin skin, easy bruising, and poor wound repair.

Abdominal striae reflect structural weakening during tissue expansion.

Bone resorption contributes to osteoporosis and fragility fractures.

Findings are mechanistically linked to prolonged glucocorticoid exposure.

Slide 22 · Cushing syndrome: Metabolic and immune effects

Hyperglycemia follows increased gluconeogenesis and reduced cellular glucose uptake.

Hypertension can be an early, nonspecific presenting feature.

Immune suppression increases susceptibility to infection.

Mood disturbance, menstrual changes, and hirsutism broaden the clinical spectrum.

Slide 23 · Cushing syndrome: Morphology by pathogenesis

Cause

Adrenal appearance

Explanation

Exogenous glucocorticoids

Bilateral cortical atrophy

Pituitary ACTH suppression

Pituitary / ectopic ACTH

Bilateral diffuse cortical hyperplasia

Sustained trophic stimulation

Primary bilateral nodular disorder

Macro- or micronodular hyperplasia

Autonomous steroidogenic signaling

Cortisol-secreting tumor

Unilateral lesion; residual cortex atrophic

Tumor cortisol suppresses ACTH

Slide 24 · Adrenal hyperplasia has recognizable patterns

Diffuse ACTH-dependent enlargement creates a broadened cortex, sometimes with subtle nodularity.

Macronodular hyperplasia contains prominent cortical nodules of variable sizes.

Micronodular hyperplasia may show dark lipofuscin-containing nodules with atrophic intervening tissue.

These patterns should not be equated simply because all can cause excess cortisol.

Slide 25 · Biochemical evidence precedes localization

A 24-hour urinary free cortisol increase supports hypercortisolism.

Loss of late-night cortisol nadir may be demonstrated with midnight salivary cortisol.

A low-dose dexamethasone suppression test may document failure to suppress.

Testing must be interpreted in clinical context before selecting adrenal or pituitary imaging.

Slide 26 · After confirming hypercortisolism: Use ACTH

Demonstrate cortisol excess

Determine plasma ACTH

Choose ACTH-dependent or -independent workup

Suppressed ACTH favors autonomous adrenal cortisol production or exogenous steroid exposure.

Nonsuppressed ACTH requires localization of pituitary versus ectopic secretion.

Suppression tests alone may be imperfect; Additional sampling may sometimes be needed.

Slide 27 · Cushing disease versus ectopic ACTH secretion

Pituitary source

Pituitary corticotroph neoplasm

ACTH-dependent cortisol excess

Bilateral adrenocortical hyperplasia

May suppress with higher-dose dexamethasone

Ectopic source

Nonpituitary ACTH-producing tumor

ACTH-dependent cortisol excess

Bilateral adrenocortical hyperplasia

Often resists high-dose dexamethasone suppression

High-dose suppression is not a definitive standalone discriminator.

Slide 28 · Hyperaldosteronism: Two fundamentally different mechanisms

Primary: Autonomous adrenal aldosterone secretion suppresses renin.

Secondary: Increased renin–angiotensin stimulation drives aldosterone release.

Both can cause sodium retention, volume expansion, and hypertension.

Distinguishing primary from secondary disease prevents erroneous etiologic classification.

Slide 29 · Renal consequences of aldosterone excess

Increased aldosterone

Na⁺ and water retention

Volume expansion / hypertension

Aldosterone stimulates mineralocorticoid receptor-mediated tubular sodium reabsorption.

Enhanced potassium excretion can produce hypokalemia.

Hypokalemia is not obligatory; Normal potassium does not exclude primary aldosteronism.

Slide 30 · Primary aldosteronism: Major source categories

Category

Defining pathologic setting

Important distinction

Bilateral idiopathic disease

Bilateral glomerulosa-type hyperplasia

Commonest source in the textbook

Aldosterone-producing adenoma

Usually solitary, small cortical adenoma

Conn syndrome

Familial forms

Inherited alterations to steroidogenesis

Multiple genetic subtypes

Adrenocortical carcinoma

Malignant autonomous production

Rare cause

Slide 31 · Conn syndrome: Aldosterone-producing adenoma

Typically a small, solitary, circumscribed bright-yellow cortical tumor.

Microscopy often resembles lipid-rich zona fasciculata rather than native glomerulosa.

ACTH secretion is usually not suppressed, so surrounding cortex is not typically atrophic.

A lesion’s size and cytology cannot independently establish its secretory status.

Slide 32 · KCNJ5 alterations: An aldosterone-producing mechanism

Mutant K⁺ channel

Loss of ion selectivity / depolarization

Ca²⁺-linked aldosterone synthase activation

Recurrent somatic KCNJ5 mutations in aldosterone-producing adenomas.

The effect is sustained aldosterone biosynthesis rather than simple trophic proliferation.

Slide 33 · Familial hyperaldosteronism type I

CYP11B1-responsive promoter

Chimeric CYP11B1–CYP11B2 regulation

ACTH-driven aldosterone synthase

Glucocorticoid-remediable aldosteronism links aldosterone synthesis to pituitary ACTH.

Promoter rearrangement—not cortical destruction—creates aberrant hormone regulation.

Slide 34 · Primary and secondary hyperaldosteronism

Primary: Adrenal autonomy

Aldosterone elevated

Renin suppressed

Adrenal adenoma or bilateral hyperplasia

Hypertension; K⁺ may be normal

Secondary: Renin-angiotensin drive

Aldosterone elevated

Renin elevated / activated

Renal hypoperfusion, edema states, or related stimuli

Correction of underlying driver is central

Slide 35 · Morphology: Bilateral glomerulosa hyperplasia

The cortex may show subtle bilateral enlargement rather than a dominant mass.

Glomerulosa-like cells expand in diffuse and focal patterns.

Wedge-shaped hyperplastic foci may extend inward from the gland periphery.

The microscopic differential includes a discrete aldosterone-producing adenoma.

Slide 36 · Hyperaldosteronism: Cardiovascular consequences

Persistent aldosterone-mediated volume expansion elevates blood pressure.

The textbook links the syndrome with cardiac hypertrophy and cardiovascular events.

Renal potassium wasting can cause weakness, paresthesias, or arrhythmic risk.

Severity of hypertension and potassium concentration alone do not reliably identify the cause.

Slide 37 · Evaluating suspected primary hyperaldosteronism

Clinical suspicion

Aldosterone : Renin assessment

Confirm autonomous secretion

Elevated aldosterone relative to suppressed renin is a central biochemical clue.

Positive screening generally requires appropriate confirmation and subtype evaluation.

Preanalytic, physiologic, and medication-related confounding can influence testing.

Slide 38 · The adrenal cortex is a source of androgen precursors

Zona reticularis generates dehydroepiandrosterone and androstenedione.

Peripheral conversion contributes biologically active androgens.

ACTH regulates adrenal androgen output.

Marked virilization may indicate congenital steroidogenic defects or an androgen-producing neoplasm.

Slide 39 · Androgen-secreting neoplasms: Interpret the phenotype

Adrenocortical tumors can produce virilization, occasionally with cortisol excess.

A virilizing adrenal neoplasm is more likely to be carcinoma than adenoma.

Hormone production must be established biochemically, not deduced from appearance alone.

Morphology is evaluated separately for evidence of malignant growth.

Slide 40 · Congenital adrenal hyperplasia: Feedback mechanism

Steroidogenic enzyme deficiency

Reduced cortisol feedback

Raised ACTH and bilateral hyperplasia

Excess androgen pathway flux

CAH encompasses inherited steroid biosynthetic disorders.

Mineralocorticoid deficiency occurs in some, not all, enzyme defects.

The clinical outcome depends on residual enzyme activity and affected pathways.

Slide 41 · 21-hydroxylase deficiency: Two blocked outputs

CYP21A2-associated enzyme defect

Reduced cortisol ± aldosterone

ACTH elevation and androgen excess

21-hydroxylase is required in the glucocorticoid and mineralocorticoid pathways.

Residual activity determines whether salt wasting accompanies virilization.

This as the predominant genetic cause of CAH.

Slide 42 · 21-hydroxylase deficiency: Clinical phenotypes

Phenotype

Cortisol / aldosterone effect

Typical presentation

Classic salt-wasting

Marked deficiency of both hormones

Neonatal dehydration, hypotension, hyperkalemia

Classic simple-virilizing

Cortisol deficient; mineralocorticoid function sufficient

Genital virilization without salt crisis

Nonclassic

Partial enzyme deficiency

Later hirsutism, acne, menstrual changes

Slide 43 · Salt-wasting CAH is a neonatal emergency

Severe mineralocorticoid deficiency produces sodium loss and hyperkalemia.

Volume depletion can progress to hypotension, acidosis, and circulatory collapse.

Affected newborns may appear stable initially because placental and maternal physiology maintained fluid balance.

Cortisol insufficiency and androgen excess coexist.

Slide 44 · Simple-virilizing CAH: Cortisol feedback failure

Residual mineralocorticoid synthesis prevents the classic salt-wasting crisis.

Deficient cortisol feedback sustains excess ACTH secretion.

Androgen overproduction can produce genital virilization or precocious pubertal changes.

Absence of salt wasting does not mean the cortisol axis is normal.

Slide 45 · Nonclassic CAH: Partial steroidogenic impairment

A partial 21-hydroxylase deficiency may present beyond infancy.

Hirsutism, acne, oligomenorrhea, and menstrual irregularities are typical clues.

Presentation overlaps with common alternative causes of hyperandrogenism.

The diagnosis requires evaluation of steroid biosynthesis rather than appearance alone.

Slide 46 · CAH morphology follows chronic ACTH stimulation

Both adrenal glands may be markedly enlarged and nodular.

A lipid-depleted, brown expanded cortex is described in severe disease.

Compact eosinophilic cells mingle with lipid-containing cortical cells.

Anterior pituitary corticotroph hyperplasia can accompany chronic low cortisol feedback.

Slide 47 · Why glucocorticoid replacement reduces virilization

Replace deficient glucocorticoid

Restore pituitary feedback

Lower ACTH

Lower adrenal androgen drive

Replacement treats cortisol deficiency and limits inappropriate ACTH-mediated stimulation.

Salt-wasting forms also require mineralocorticoid replacement.

The therapeutic logic directly follows the endocrine feedback defect.

Slide 48 · Adrenocortical insufficiency: Classify by level

Primary insufficiency arises from cortical loss or failure of steroid biosynthesis.

Secondary insufficiency reflects inadequate pituitary ACTH output.

Primary disease can present acutely as a crisis or chronically as Addison disease.

Aldosterone preservation in secondary disease has important diagnostic implications.

Slide 49 · Acute adrenal crisis: Stress exceeds reserve

Reduced cortical reserve

Severe physiologic stress

Inadequate cortisol response

Circulatory deterioration

Acute decompensation may complicate established chronic adrenal insufficiency.

Rapid steroid withdrawal can precipitate crisis in ACTH-suppressed patients.

Bilateral hemorrhagic destruction is another potentially catastrophic mechanism.

Slide 50 · Primary acute insufficiency: Common precipitating settings

Unrecognized chronic cortisol deficiency stressed by infection or illness.

Abrupt discontinuation of long-term exogenous glucocorticoids.

Bilateral adrenal hemorrhage, including DIC-associated injury or severe infection.

Immune-checkpoint therapy may injure adrenal or pituitary tissue.

Slide 51 · Waterhouse–Friderichsen syndrome

A fulminant infection classically associated with meningococcal septicemia.

Rapid shock and DIC accompany extensive purpura.

Massive bilateral adrenal hemorrhage destroys steroidogenic reserve.

It is a clinicopathologic emergency; Delayed recognition may be fatal.

Slide 52 · Waterhouse–Friderichsen: Tissue injury sequence

Septicemia / endothelial injury

DIC and adrenal hemorrhage

Loss of viable cortex

Acute adrenal failure

Hemorrhage can begin near the medullary venous sinusoids and extend into the cortex.

Gross glands may be largely replaced by clotted blood with little preserved architecture.

Slide 53 · Addison disease: Progressive primary cortical loss

Chronic adrenal insufficiency follows progressive destruction of the cortex.

Substantial functional tissue may be lost before the clinical syndrome becomes evident.

Etiologies include autoimmunity, infection, infiltration, hemorrhage, and metastatic disease.

Primary hormone deficits produce high compensatory ACTH and may affect aldosterone.

Slide 54 · Autoimmune adrenalitis: Loss of steroidogenic cells

Immune-mediated cortical damage

Reduced steroid synthesis

Increased pituitary ACTH

Hyperpigmentation / insufficiency

Antibodies to steroidogenic enzymes, including 21-hydroxylase, may support an autoimmune process.

Autoimmune adrenalitis can be isolated or accompany polyendocrine autoimmunity.

Slide 55 · APS-1 links adrenal autoimmunity to central tolerance

The syndrome is associated with defects in the AIRE gene.

Defective thymic expression of tissue antigens impairs deletion of autoreactive T cells.

Adrenalitis can coexist with hypoparathyroidism and mucocutaneous candidiasis.

The source explains candidiasis by impaired Th17-related antifungal immunity.

Slide 56 · Autoimmune polyendocrine syndromes

APS-1

AIRE-related central tolerance defect

Adrenalitis and hypoparathyroidism may occur

Chronic mucocutaneous candidiasis

Ectodermal abnormalities can be present

APS-2

Adrenalitis with autoimmune thyroid disease

Type 1 diabetes may coexist

More frequent than APS-1

No defining candidiasis or ectodermal dysplasia

Slide 57 · Other causes of primary chronic adrenal loss

Tuberculosis and fungal infection may destroy both glands.

Opportunistic infections are especially relevant in immunocompromised patients.

Metastatic carcinoma can extensively replace adrenal parenchyma.

Amyloid, granulomatous disease, iron deposition, and inherited disorders form additional mechanisms.

Slide 58 · Primary Addison disease: Phenotype from hormone loss

Weakness, fatigue, gastrointestinal disturbance, and hypotension are common.

ACTH elevation produces hyperpigmentation in primary disease.

Mineralocorticoid deficiency can contribute to salt loss and hyperkalemia.

Clinical severity depends on the extent and tempo of cortical destruction.

Slide 59 · Secondary adrenal insufficiency: Inadequate ACTH

Pituitary or hypothalamic injury reduces ACTH drive to the cortex.

Long-term exogenous glucocorticoids can suppress endogenous ACTH.

Cortisol and adrenal androgen output fall, but aldosterone is usually preserved.

The absence of hyperpigmentation and marked hyperkalemia helps distinguish secondary disease.

Slide 60 · Primary versus secondary adrenal insufficiency

Feature

Primary cortical failure

Secondary ACTH deficiency

ACTH

High (loss of cortisol feedback)

Low or inappropriately normal

Cortisol

Reduced

Reduced

Aldosterone

Often reduced

Usually normal / near normal

Hyperpigmentation

May be present

Not characteristic

Hyperkalemia

May occur

Not characteristic

Slide 61 · Cosyntropin response tests cortical reserve

Administer synthetic ACTH

Measure cortisol response

Interpret adrenal reserve and context

Primary cortical destruction reduces cortisol responsiveness.

Long-standing secondary ACTH deficiency can also blunt the response through adrenal atrophy.

Recent-onset secondary deficiency may retain an initially normal response.

Slide 62 · Morphology of secondary insufficiency

Loss of sustained ACTH stimulation shrinks cortisol-producing cortical compartments.

The gland can be small and flattened while retaining yellow cortical tissue.

Zona glomerulosa is relatively preserved because aldosterone does not depend primarily on ACTH.

A normal-size gland does not exclude recent-onset secondary dysfunction.

Slide 63 · Adrenocortical neoplasms: A functional spectrum

Many cortical adenomas are nonfunctional and incidentally detected.

Functioning lesions may cause cortisol or aldosterone excess.

Pronounced virilization raises concern for adrenocortical carcinoma.

A diagnosis of functionality requires clinical and biochemical evidence.

Slide 64 · Adrenocortical adenoma: Core morphologic features

A circumscribed yellow to yellow-brown nodule often resembles normal steroidogenic cortex.

Lipid-rich cells can have pale, vacuolated cytoplasm.

Limited nuclear pleomorphism can be present without establishing malignancy.

Mitotic activity is generally low; Hormone function is not determined by H&E appearance.

Slide 65 · Carcinoma: Destructive growth changes the diagnosis

Adrenocortical carcinoma is often a large, infiltrative tumor effacing the gland.

Cut surfaces may be variegated with hemorrhage, necrosis, and cystic change.

Venous, lymphatic, and distant invasion are important malignant behaviors.

Smaller or better-differentiated carcinomas may be morphologically challenging.

Slide 66 · Cortical adenoma versus carcinoma: Overview

Criterion

Adenoma (typical)

Carcinoma (typical)

Gross border

Well circumscribed

Often infiltrative / poorly demarcated

Gross cut surface

Yellow, lipid rich

Variegated necrosis or hemorrhage

Cytologic variability

Mild atypia possible

May be markedly atypical or deceptively bland

Biologic behavior

Noninvasive

Can invade veins and metastasize

Slide 67 · Carcinoma genetics: Separate susceptibility from diagnosis

Li–Fraumeni syndrome predisposes to carcinoma through germline TP53 alterations.

Beckwith–Wiedemann syndrome links adrenal tumor susceptibility to IGF2 imprinting biology.

Somatic TP53 changes and elevated IGF2 expression may also occur in sporadic tumors.

Genetic associations are not substitutes for integrated morphologic and clinical assessment.

Slide 68 · Cortical lineage versus adrenal metastasis

Metastases to the adrenal are more frequent than primary adrenocortical carcinomas.

Cortical tumors may express steroidogenic factor 1 (SF-1) and inhibin-α.

Immunohistochemical results should be interpreted within a differential, not in isolation.

Clinical imaging and evidence of an extra-adrenal primary are crucial for classification.

Slide 69 · Adrenal incidentaloma is a clinical discovery pattern

Imaging performed for unrelated complaints can reveal a silent adrenal mass.

Many incidental lesions are small, nonsecretory cortical adenomas.

A subset produces cortisol without overt classic Cushing features: Mild autonomous cortisol secretion.

Risk appraisal combines hormone evaluation with radiologic and pathologic assessment.

Slide 70 · Adrenal myelolipoma and cysts: Relevant mimics

Myelolipoma is a benign admixture of mature adipose and hematopoietic tissue.

Some myelolipomas become large but are frequently incidentally discovered.

Cysts and cystic tumor degeneration can present as apparently nonfunctional masses.

Not all adrenal masses are steroid-producing cortical neoplasms.

Slide 71 · An integrated adrenal pathology checklist

Question

Interpretation

Next intellectual step

What is produced?

Cortisol, aldosterone, androgen, or none

Document biochemical functionality

What drives production?

ACTH, renin–angiotensin, or autonomous lesion

Interpret endocrine feedback

What is the tissue response?

Atrophy, diffuse/nodular hyperplasia, mass

Describe native morphology

Is it malignant?

Invasion and integrated tumor features

Evaluate carcinoma versus metastasis

Slide 72 · Case integration: Hypertension and low renin

Hypertension ± hypokalemia

Elevated aldosterone relative to renin

Consider primary aldosteronism

An adenoma and bilateral glomerulosa hyperplasia are different pathologic subtypes.

Normal potassium does not exclude the syndrome.

Biochemical subtype localization must precede causal attribution to an imaging nodule.

Slide 73 · Case integration: Cortisol excess with low ACTH

Cushing phenotype and hypercortisolism

Low ACTH

Investigate exogenous or adrenal source

A cortisol-producing adrenal neoplasm may suppress the contralateral cortex.

By contrast, exogenous glucocorticoids may produce bilateral ACTH-dependent atrophy.

A mass is not automatically the cause without biochemical correlation.

Slide 74 · Case integration: Shock and adrenal hemorrhage

Sepsis with purpura and DIC

Bilateral adrenal hemorrhage

Acute cortical destruction / crisis

Waterhouse–Friderichsen syndrome is an urgent clinical-pathologic diagnosis.

Massive hemorrhage can obliterate the usual adrenal architecture.

Its mechanism is not the chronic autoimmune destruction of Addison disease.

Slide 75 · Integrated principles of adrenal cortical pathology

Zone-specific steroid production predicts the functional syndrome.

Pituitary ACTH explains both hyperplasia during stimulation and atrophy during suppression.

Primary versus secondary failure differs in ACTH, aldosterone, and pigmentation patterns.

Adrenal neoplasm classification requires morphology plus hormonal and clinical evidence.

Slide 76 · Primary reference and scope

Robbins, Cotran & Kumar: Pathologic Basis of Disease. 11th edition (2026).

Chapter 24, The Endocrine System: Adrenal glands and adrenal cortex, printed pp. 1012–1023.

Source excerpt transcribed in the project’s robbins.md file; diagrams here are original editable teaching schematics.

Original textbook photomicrographs were not reproduced because source image files and reuse rights were unavailable.