Hypercortisolism Cushing Syndrome

Slide 1 · Hypercortisolism

Cushing syndrome

Etiology • Pathogenesis • Morphology • Clinical correlation

An adrenal pathology lecture

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Cortisol excess: The defining abnormality

Cushing syndrome denotes the clinical consequences of sustained glucocorticoid excess.

Exogenous corticosteroid exposure and endogenous cortisol overproduction cause a similar systemic phenotype.

Determining the source of hormone excess explains the observed adrenal morphology.

Slide 3 · The adrenal cortex has functionally distinct zones

Capsule

Zona glomerulosa

Zona fasciculata

Zona reticularis

Medulla

Zona fasciculata is the principal source of cortisol.

Zona reticularis contributes to glucocorticoid production and secretes sex steroids.

Zona glomerulosa primarily makes aldosterone and is relatively ACTH independent.

Slide 4 · The hypothalamic–pituitary–adrenal axis

Hypothalamus

CRH

Pituitary corticotroph

ACTH

Adrenal cortex

Cortisol

Negative feedback: Cortisol inhibits CRH and ACTH release

CRH drives pituitary ACTH; ACTH stimulates the adrenal cortisol-producing cortex.

Circulating cortisol restrains upstream secretion through negative feedback.

Slide 5 · Negative feedback predicts the ACTH result

Autonomous cortisol or exogenous steroid

Negative feedback at pituitary

Suppressed endogenous ACTH

Low ACTH points toward an ACTH-independent adrenal source or exogenous exposure.

In ACTH-dependent disease, the driver persists despite high cortisol.

Slide 6 · Etiologic classification starts with steroid exposure

Exogenous

Therapeutic glucocorticoid exposure

Most frequent overall source

Suppression of native ACTH

Endogenous

Internally produced cortisol excess

Requires ACTH-based etiologic subdivision

Pituitary, ectopic, or adrenal source

The commonest cause of the syndrome is iatrogenic glucocorticoid administration.

Slide 7 · Endogenous Cushing syndrome: Two mechanistic groups

ACTH dependent

Pituitary ACTH-producing neoplasm

Ectopic tumor-associated ACTH or CRH

Usually bilateral adrenal hyperplasia

ACTH independent

Cortisol-secreting adrenal neoplasm

Primary bilateral nodular hyperplasia

Suppressed ACTH; Lesion-driven cortisol

Slide 8 · ACTH level is a mechanistic discriminator

Confirmed cortisol excess

Measure circulating ACTH

Classify ACTH dependence

Low ACTH favors adrenal autonomy or exogenous suppression.

Normal or increased ACTH in the face of hypercortisolism is inappropriate and suggests ACTH dependence.

Slide 9 · Exogenous glucocorticoids: The dominant cause

Iatrogenic Cushing syndrome results from the administration of glucocorticoids.

Steroid exposure can reproduce the systemic effects of endogenous hypercortisolism.

Suppression of pituitary ACTH explains the accompanying adrenal cortical atrophy.

A medication history is integral to the etiologic assessment.

Slide 10 · Iatrogenic hypercortisolism suppresses native ACTH

Administered steroid

Pituitary ACTH suppression

Bilateral cortical atrophy

Decreased ACTH trophic stimulation affects the zona fasciculata and zona reticularis.

Zona glomerulosa is generally preserved because its control is largely ACTH independent.

Slide 11 · Cortical atrophy in steroid-induced disease

Paired adrenal glands

Left adrenal

Right adrenal

Schematic anatomy — not a gross specimen

Both adrenal cortices become thin when ACTH is chronically suppressed.

The fasciculata and reticularis lose trophic support.

The glomerulosa retains near-normal thickness.

Slide 12 · Endogenous causes follow a distinct hierarchy

Cause

Control mechanism

Typical adrenal effect

Pituitary corticotroph tumor

ACTH dependent

Bilateral cortical hyperplasia

Ectopic ACTH/CRH production

ACTH dependent

Bilateral cortical hyperplasia

Cortisol-producing adrenal tumor

ACTH independent

Tumor + suppressed nonneoplastic cortex

Primary bilateral nodular hyperplasia

ACTH independent

Bilateral macronodules or micronodules

Slide 13 · Cushing disease is specifically pituitary ACTH excess

Cushing disease refers to hypercortisolism caused by pituitary corticotroph ACTH production.

An ACTH-secreting pituitary neuroendocrine tumor accounts for most pituitary cases.

Persistent ACTH stimulation drives bilateral adrenal cortical growth and cortisol release.

Slide 14 · Pituitary disease dominates endogenous cases

Pituitary corticotroph neoplasms account for approximately 60%–70% of endogenous hypercortisolism description.

Cushing disease is reported more frequently in females, often in young adulthood.

These epidemiologic patterns provide context but do not replace biochemical testing.

Textbook proportion is source-specific; Not presented as a current population registry estimate.

Slide 15 · Pituitary cellular pathology is not uniform

Most cases

Discrete ACTH-producing pituitary neuroendocrine tumor

Typically a small adenoma

Less common

Pituitary macroadenoma

Rare corticotroph hyperplasia without a discrete tumor

Slide 16 · Corticotroph hyperplasia may follow CRH excess

Excess hypothalamic or ectopic CRH

Pituitary corticotroph stimulation

ACTH-driven adrenal hyperplasia

Corticotroph hyperplasia may arise primarily or from excessive CRH drive.

A CRH-producing lesion can therefore indirectly produce an ACTH-dependent Cushing phenotype.

Slide 17 · ACTH drives a bilateral adrenal response

Paired adrenal glands

Left adrenal

Right adrenal

Schematic anatomy — not a gross specimen

Long-standing ACTH stimulation thickens the adrenal cortex.

Both glands typically enlarge rather than a unilateral tumor becoming dominant.

This tissue response generates excess cortisol.

Slide 18 · Cushing syndrome and Cushing disease are not synonyms

Cushing syndrome

All causes of glucocorticoid excess

Can be iatrogenic, ACTH dependent or independent

Cushing disease

Specific pituitary ACTH-driven etiology

A subset of endogenous Cushing syndrome

Slide 19 · Ectopic ACTH is a tumor-associated source

Nonpituitary neoplasm

Ectopic ACTH production

Bilateral adrenal stimulation

The source lies outside the pituitary.

The adrenal glands are secondarily hyperplastic rather than the primary autonomous driver.

Slide 20 · Neoplasms implicated in ectopic ACTH production

Neoplasm

Textbook association

Small-cell carcinoma of lung

Frequently responsible

Carcinoid / neuroendocrine tumor

Recognized source

Medullary thyroid carcinoma

Reported association

Pancreatic neuroendocrine neoplasm

Reported association

Slide 21 · Ectopic CRH can also produce hypercortisolism

Tumor releases CRH

Pituitary secretes ACTH

Adrenal cortex produces cortisol

The ectopic tumor supplies CRH rather than necessarily supplying ACTH.

ACTH remains the immediate pituitary-to-adrenal signal.

Slide 22 · Pituitary and ectopic ACTH share an adrenal pattern

Pituitary ACTH

Pituitary lesion is primary

Bilateral cortical hyperplasia

May evolve gradually

Ectopic ACTH

Nonpituitary neoplasm is primary

Bilateral cortical hyperplasia

Rapid tumor course may limit enlargement

Slide 23 · Adrenal neoplasms generate ACTH-independent cortisol

Autonomous adrenocortical lesion

Increased cortisol

Pituitary ACTH suppression

Adenomas and carcinomas are the principal tumor causes.

Contralateral and adjacent nonneoplastic cortex lose ACTH trophic stimulation.

Slide 24 · ACTH-independent syndrome has a biochemical hallmark

High cortisol occurs together with low circulating ACTH.

The inappropriate cortisol secretion originates in the adrenal cortex.

The hormone pattern should be interpreted together with exposure history and morphology.

Slide 25 · Cortisol-producing adenoma versus carcinoma

Adrenocortical adenoma

Generally small and well circumscribed

Yellow appearance; Cells resemble fasciculata

Can be hormonally functional

Adrenocortical carcinoma

Generally larger and unencapsulated

Anaplastic malignant morphology

Can produce marked hypercortisolism

Slide 26 · Feedback suppression surrounds a functional adrenal tumor

Paired adrenal glands

Tumor-bearing gland

Contralateral atrophy

Schematic anatomy — not a gross specimen

A functional tumor releases cortisol without normal ACTH control.

ACTH suppression atrophies the adjacent nonneoplastic cortex.

The contralateral gland also becomes atrophic.

Slide 27 · Genetic alterations in adrenocortical carcinoma

Gene

Alteration described in source

CTNNB1

Recurrent activating mutations

TP53

Recurrent inactivating mutations

MEN1

Recurrent inactivating mutations

PRKAR1A

Recurrent inactivating mutations

Slide 28 · PRKAR1A links cortisol-producing lesions through cAMP

PRKAR1A dysfunction

Increased cAMP signaling

Cortical growth / cortisol output

Alterations are described in adenomas, carcinomas and micronodular hyperplasia.

A shared signaling mechanism does not imply that these lesions have identical morphology or behavior.

Slide 29 · Primary adrenal hyperplasia can be ACTH independent

Macronodular

Prominent bilateral nodules

Usually >10 mm diameter

May involve aberrant hormone receptor signaling

Micronodular

Small nodules, typically <10 mm

May be darkly pigmented

Often linked to PRKAR1A-pathway disease

Slide 30 · Bilateral macronodular adrenal hyperplasia

Paired adrenal glands

Left adrenal

Right adrenal

Schematic anatomy — not a gross specimen

The cortex is remodeled by prominent nodules of variable size, often 10–30 mm.

Between gross nodules, microscopic nodularity may persist.

Lipid-rich and lipid-poor cells can coexist within nodules.

Slide 31 · ARMC5: A two-hit mechanism in some BMAH

Germline ARMC5 variant

Somatic loss of second allele

Adrenal nodular growth

Familial BMAH can show ARMC5 tumor-suppressor disruption.

The textbook also reports germline variants in some apparently sporadic cases.

Slide 32 · Aberrant G-protein-coupled receptors in BMAH

Ectopic receptor expression

Non-ACTH hormone stimulation

Cortisol secretion

Examples described include gastric inhibitory polypeptide, LH and vasopressin.

Such lesions need not be entirely autonomous from hormonal signals.

Slide 33 · Micronodular cortical hyperplasia is often pigmented

Paired adrenal glands

Left adrenal

Right adrenal

Schematic anatomy — not a gross specimen

Small cortical nodules are commonly brown-black because of lipofuscin pigment.

Intervening cortex may be atrophic.

Pigmented nodules are not interchangeable with macronodular hyperplasia.

Slide 34 · Pigmented nodular disease and Carney complex

Primary pigmented nodular adrenocortical disease may occur independently.

It can also occur within Carney complex, a multisystem syndrome with endocrine and nonendocrine neoplasms.

Both settings are commonly associated with PRKAR1A alterations.

Slide 35 · CAMP-pathway activation: Shared signal, different lesions

PRKAR1A / GNAS pathway effect

Increased intracellular cAMP

Nodular adrenocortical hyperfunction

The source links PRKAR1A inactivation and activating GNAS alterations to increased cAMP signaling.

Genotype and phenotype are not one-to-one; Do not infer a mutation solely from histology.

Slide 36 · Bilateral nodular hyperplasia: Pathologic comparison

Feature

Macronodular

Micronodular

Nodule size

Usually >10 mm; often 10–30 mm

Often 1–3 mm; typically <10 mm

Gross pattern

Numerous prominent nodules

Multiple small brown-black nodules

Intervening tissue

May show microscopic nodules

Often atrophic

Pigmentation

Not defining

Lipofuscin often prominent

Slide 37 · Crooke hyaline change in pituitary corticotrophs

Typical corticotroph

Crooke hyaline change

Schematic — not a histologic specimen

A common pituitary response to prolonged glucocorticoid excess.

Corticotroph cytoplasm becomes pale and homogeneous rather than normally granular-basophilic.

Accumulation of intermediate keratin filaments produces the change.

Slide 38 · Adrenal morphology encodes the underlying source

Driving mechanism

Expected adrenal finding

Exogenous glucocorticoids

Bilateral cortical atrophy

Pituitary / ectopic ACTH

Bilateral diffuse cortical hyperplasia

Primary nodular hyperplasia

Bilateral macro- or micronodules

Functional adrenal neoplasm

Cortical tumor; nonneoplastic cortex atrophic

Slide 39 · Diffuse cortical hyperplasia: Gross pattern

Paired adrenal glands

Left adrenal

Right adrenal

Schematic anatomy — not a gross specimen

Both glands are enlarged, sometimes subtly.

Yellow cortical thickening may show mild nodularity.

This differs from prominent large-nodule macronodular disease.

Slide 40 · Diffuse hyperplasia: Lipid-poor and lipid-rich zones

Simplified cellular schematic

Schematic — not a histologic specimen

Expanded inner lipid-poor zona reticularis has compact eosinophilic cells.

An outer lipid-rich zone contains vacuolated cells resembling zona fasciculata.

Vacuolated nodules contribute to the yellow gross appearance.

Slide 41 · Micronodular disease: Pigmented cortical nodules

Simplified cellular schematic

Schematic — not a histologic specimen

Dark micronodules can contain lipofuscin pigment.

Nodules are surrounded by relatively atrophic nonnodular cortex.

A cellular schematic illustrates pigment distribution; It is not H&E evidence.

Slide 42 · Functional adenomas resemble nonfunctioning adenomas

Grossly, adenomas are generally yellow and encapsulated or well circumscribed.

Their cells resemble normal zona fasciculata cells.

Function cannot be established from routine architecture alone.

Most adenomas weigh less than 30 g; Do not use mass alone as a malignancy criterion.

Slide 43 · Adrenocortical carcinoma: Malignant morphology

Carcinomas tend to be much larger than adenomas and often lack a capsule.

They exhibit malignant cytologic and architectural features rather than a unique cortisol-secreting morphology.

Cortisol production may be particularly marked in some carcinomas.

Masses frequently exceeding 200–300 g, without making weight a standalone diagnostic test.

Slide 44 · Why nonneoplastic cortex atrophies beside a tumor

Functional adrenal tumor

Systemic cortisol excess

ACTH feedback suppression

The adjacent cortex and the contralateral gland receive less ACTH.

This is a hormone-feedback effect, not necessarily direct destruction of surrounding tissue.

Slide 45 · Distinct patterns can be read as a morphology map

Adrenal image pattern

Most relevant etiologic inference

Important qualification

Bilateral small glands

Exogenous suppression

Integrate medication history

Bilateral diffuse enlargement

ACTH-driven cortisol excess

Pituitary and ectopic ACTH overlap

Bilateral discrete nodules

Primary nodular disease

Macro-/micronodular subtyping

Unilateral cortical neoplasm

Adrenal autonomy

Assess adjacent/contralateral atrophy

Slide 46 · Clinical syndrome develops gradually

Onset may be insidious, and early findings are relatively nonspecific.

Weight gain and hypertension may precede the full constellation of signs.

Sustained cortisol excess produces the characteristic multisystem phenotype over time.

Slide 47 · Redistribution of adipose tissue produces a pattern

Cortisol excess

Central fat accumulation

Truncal obesity / moon facies

Posterior cervical and upper-back fat deposition contributes to the “buffalo hump.”

Regional adipose changes are more informative as a constellation than as isolated findings.

Slide 48 · Selective type II myofiber atrophy causes weakness

Cortisol-associated muscle catabolism

Type II myofiber atrophy

Proximal limb weakness

Muscle mass declines despite central weight gain.

Proximal weakness is an important functional consequence of chronic glucocorticoid excess.

Slide 49 · Glucose dysregulation follows metabolic hormone action

Increased gluconeogenesis

Reduced cellular glucose uptake

Hyperglycemia

Secondary diabetes and glucosuria may develop.

Polydipsia can reflect the metabolic consequences of increased circulating glucose.

Slide 50 · Skin fragility reflects impaired structural maintenance

Glucocorticoid catabolism

Collagen loss

Thin, easily bruised skin

Poor wound healing and conspicuous abdominal striae reflect matrix and tissue fragility.

These changes connect superficial clinical signs with collagen metabolism.

Slide 51 · Bone resorption explains osteoporotic complications

Sustained cortisol excess

Bone resorption

Osteoporosis / fractures

Skeletal weakening can produce back pain.

Fracture susceptibility is an important consequence of chronic disease.

Slide 52 · Glucocorticoids impair antimicrobial defense

Cortisol excess

Suppressed immune response

Increased infection risk

The clinical susceptibility follows pharmacologic and endogenous glucocorticoid immunosuppression.

The presence of infection does not specify which mechanism produced the excess cortisol.

Slide 53 · Neuropsychiatric and reproductive effects

Neuropsychiatric

Mood instability

Depressive symptoms

Potential severe psychotic features

Reproductive / androgenic

Menstrual irregularity

Hirsutism

Changes in libido

Slide 54 · Clinical feature frequencies: Selected source examples

Finding

Frequency reported in textbook table

Weight gain / obesity

95%

Facial plethora

90%

Hypertension

75%

Easy bruising

65%

Glucose intolerance

60%

Weakness

60%

Historical source estimates; Not sensitivities or a contemporary population prevalence study.

Slide 55 · Clinical signs require biochemical corroboration

Obesity, hypertension and hyperglycemia individually have many possible causes.

Concordant findings spanning skin, muscle, fat distribution and bone increase clinical suspicion.

Clinical recognition initiates biochemical evaluation; It does not establish etiology.

Slide 56 · Twenty-four-hour urinary free cortisol

Increased urinary free cortisol is one biochemical indication of hypercortisolism.

The collection integrates free cortisol excretion across a full day.

Interpret biochemical testing in clinical context rather than from appearance alone.

Urinary free cortisol among the central tests for syndrome recognition.

Slide 57 · Loss of cortisol circadian regulation

Normal diurnal rhythm

Loss of midnight nadir

Elevated late-night salivary cortisol

Cushing syndrome disturbs the normal diurnal pattern.

Late-night salivary cortisol is used to detect this characteristic loss of suppression.

Slide 58 · Low-dose dexamethasone suppression test

Administer 1 mg dexamethasone

Assess cortisol suppression

Failure suggests hypercortisolism

An exogenous glucocorticoid should suppress cortisol through feedback in a normal regulatory axis.

The 1-mg test as a method to identify hypercortisolism.

Slide 59 · The biochemical sequence separates two questions

Does hypercortisolism exist?

24-hour urinary free cortisol

Late-night salivary cortisol

Low-dose dexamethasone test

What causes it?

Medication exposure history

Serum ACTH level

Further investigation of pituitary, ectopic or adrenal source

Slide 60 · Serum ACTH guides etiologic evaluation

Establish cortisol excess

Measure ACTH

Investigate driving source

Low ACTH: Adrenal source or exogenous suppression.

Inappropriately normal/high ACTH: Pituitary or ectopic ACTH/CRH pathway.

Slide 61 · High-dose dexamethasone: Utility and limits

Pituitary source

Often suppresses cortisol at higher dexamethasone dose

Interpret as a tendency, not an absolute rule

Ectopic ACTH source

Often lacks suppression with higher dose

Some overlap and failures of discrimination occur

Slide 62 · Inferior petrosal sinus sampling resolves ambiguity

ACTH-dependent syndrome

Uncertain pituitary vs ectopic source

Selective venous sampling

Some ambiguous cases require inferior petrosal sinus sampling.

High-dose dexamethasone alone is not definitive.

Slide 63 · The diagnostic map integrates mechanism and morphology

Verify cortisol excess

Classify with ACTH

Correlate source and morphology

Exposure history precedes attribution to endogenous disease.

The expected adrenal pattern is an independent pathophysiologic consistency check.

Slide 64 · Case: Iatrogenic hypercortisolism

Teaching vignette (hypothetical)

An adult treated with prolonged systemic glucocorticoids develops truncal obesity, easy bruising and proximal weakness. The endogenous pituitary–adrenal axis is suppressed.

Clinicopathologic interpretation

Etiology: Exogenous steroid-associated Cushing syndrome.

Expected ACTH: Suppressed.

Expected adrenal morphology: Bilateral cortical atrophy.

Slide 65 · Case: Pituitary ACTH-dependent disease

Teaching vignette (hypothetical)

A young adult has progressive centripetal weight gain, proximal weakness and biochemical cortisol excess. ACTH is not suppressed, and a pituitary corticotroph tumor is identified.

Clinicopathologic interpretation

Etiology: Cushing disease.

Pituitary ACTH stimulates both adrenal cortices.

Expected adrenal pattern: Bilateral diffuse hyperplasia.

Slide 66 · Case: Autonomous adrenal tumor

Teaching vignette (hypothetical)

A patient has hypercortisolism with suppressed ACTH. A unilateral cortical tumor is identified; The opposite adrenal is small.

Clinicopathologic interpretation

Mechanism: ACTH-independent cortisol production.

Adjacent and contralateral cortical atrophy follow ACTH suppression.

Histologic assessment is needed to distinguish benign from malignant tumor.

Slide 67 · Case: Ectopic ACTH production

Teaching vignette (hypothetical)

A patient with a lung neuroendocrine malignancy develops rapidly progressive clinical hypercortisolism. ACTH is inappropriately increased.

Clinicopathologic interpretation

Consider ectopic ACTH production from the malignancy.

Expected adrenal response: Bilateral cortical hyperplasia.

Pituitary and ectopic ACTH sources can require further discrimination.

Slide 68 · Morphology–biochemistry integration

Syndrome driver

ACTH

Adrenals

Exogenous steroid

Low

Bilateral atrophy

Pituitary corticotroph

Normal/high relative to cortisol

Bilateral hyperplasia

Ectopic ACTH/CRH

Normal/high relative to cortisol

Bilateral hyperplasia

Adrenal cortisol-producing tumor

Low

Unilateral neoplasm; residual atrophy

Primary nodular hyperplasia

Low

Bilateral nodules

Slide 69 · Integrated clinicopathologic synthesis

The most common overall cause is exogenous glucocorticoid administration.

Endogenous sources are classified by ACTH dependence and can be inferred from biochemical feedback.

Adrenal atrophy, diffuse hyperplasia, nodular hyperplasia and neoplasia reflect different hormonal mechanisms.

Clinical recognition and biochemical testing must be integrated with the etiologic diagnosis.

Slide 70 · References and interpretation limits

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th edition (2026), Chapter 24, pp. 1012–1015.

Clinical-frequency examples are drawn from Table 24.8, adapted in the textbook from Newell-Price et al., Lancet (2006).

This lecture presents the supplied textbook account; contemporary guideline validation and chapter-PDF figure verification were not performed.