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Adrenal Gland Pathology

Anatomy, Histology Clinical Course

Paired Endocrine organs
Lying on Upper Pole of each Kidney enclosed in a Capsule
Normal Weight of Each Gland – 4g
Normal Adrenal Glands
Each weighing 4g
Section through Adrenal Glands
Outer Golden Yellow Cortex
Inner Red to Grey Medulla
Cortex
Zona Glomerulosa (Narrow)
(Generate Aldosterone)
Zona Fasciculata (Broad)
(Secrete Glucocorticoids )
(Principally Cortisol)
Zona Reticularis (Narrow)
(Produce Sex Steroids)
(Estrogens, Androgens)
Medulla
Compose d of Chromaffi n Cells
(Synthesize, Secrete Catecholamines)
(mainly Epinephrine)
Hypertension
Weight ↑
Central Fat Deposition in form of Truncal Obesity, Moon Facies, Buffalo Hu mp
↓ Muscle Mass, Proximal Limb Weakness
Glucose Intolerance, Diabetes
Osteoporosis
Skin Striae
Neuropsychiatric Abnormalities
Plethora
Hirsutism, Menstrual Disturbances
Diagnosis
Based on Clinical Features, Lab Findings
• ↑ 24h Urine Cortisol Level
• Loss of N ormal Diurnal Pattern of Corticol Secretion
Underlying cause is detected by estimation of
• Serum ACTH
• Urinary Steroid Excretion after administration of Dexamethasone

Diagnosis
Pathology of Adrenal Cortex Cushing Syndrome Pituitary Adrenal Ectopic
Adrenocortical Adrenocortical Adrenocortical Serum ACTH ↑ ↓ ↑
Hyperfunction Hypofunction Neoplasms ↓ Dose Steroid Not suppressed Not Suppressed Insensitive or Not
(Adrenocortical (No ↓ Urinary (No ↓ Urinary Suppressed
Insufficiency) Steroid Excretion) Steroid Excretion) (No ↓ in Urinary)
↑ Dose Steroid Suppressed Not Suppressed Insensitive or Not
Hypercorticolism 1° Adrenocortical Hyperplasia (Suppression of (No ↓ in Urinary Suppressed
(Cushing Syndrome) Insuffi ciency Adenoma Urinary Steroid) Steroid Excretion) (No ↓ in Urinary)
Hyperaldosteronism • Acute Carcinoma
Adrenogenital, Virilizing • Chronic
Syndrome 2° Adrenocortical
Insuffi ciency

Cushing Syndrome

Definition
Symptom complex is cau sed by ↑ Glucocorticoid levels
Exogenous Administration
Most common type
Endogenous
1° Hypothalamic-Pituitary Diseases associated
with Hypersecretion of ACTH (70-80%)
Hypersecretion of Cortisol by
• Adrenal Adenoma
• Adrenal Carcinoma
• Adrenal Nodular Hyperplasia
Ectopic ACTH secretion by
Non-Pituitary Neoplasm

Forms of Cushing Syndrome

Pituitary Cushing Syndrome Adrenal Cushing Syndrome

Paraneoplastic Cushing Syndrome Iatrogenic Cushi ng Syndrome

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Cushing Syndrome
Pituitary (Cushing Disease) Adrenal Paraneoplastic Iatrogenic
Endogenous Cus hing Syndrome caused by Endogenous Cus hing Syndrome (10-20%) Accounts for most of Exogenous Glucocortisol
1° Hypersecretion of ACTH (70-80%) 1° Adrenal Neoplasm 1° Cortical Hyperplasia the remaining cases of ↓

Endogenous Cus hing Suppression of

Women ↑ Adenoma
Endogenous ACTH
Frequently 20-30 y/o Carcinoma Syndrome (10%) ↓
ACTH Producing ACTH-Independent Ectopic ACTH secretion Bilateral Adrenal Atrophy
• Pituitary Microadenoma Cushing Syndrome from non -pituitary (due to lack of zona
• Pituitary Macroadenoma (>10mm)(Few) (Adrenals tumours stimulation)
Remainder – Anterior Pituitary contain foci of function autonomously) • Small Cell Carcinoma (zona fasci culata,
Corticotroph Cell Hyperplasia ↑ Serum Cortisol of Lung reticularis by ACTH)
without a discrete adenoma ↓ Serum ACTH (not Squamous Cell)
Zona Glomerulosa
1° 2° • Carcinoid Tumours
Adrenal Neoplasm • Normal Thickness
Due to Excessive Stimulation of • Medullary Carcinoma
Adenoma, Carcinoma (Eq ually Affected) • Function Independently
ACTH release from a Hypothalamic of Thyroid
Cortisol in Adrenal Carcinoma ↑ (compared Adenoma ) of ACTH
Tumour produ cing Corticotrophin Uninvolved Adrenal Gland, Opposite Gland • Islet Cell Tumours of
Releasing Hormone (CRH ) Pancreas
undergo Atrophy (due to ACTH-suppression)
↑ ACTH Adrenal Hyperplasia (1°) Adrenal Gland undergo
↓
Massive Macronodular Primary Pigmented Bilateral Cortical
Adrenal Glands Adrenocortical Disease Nodular Adrenal Hyperplasia
Hyperplasia (MMAD) Disease (↑ common in Men,
↓
↑ Cortisol (PPNAD) in 40-50 y/o)
(Hypercortisolism) Nodules > 3mm Diffuse Bilateral
(diameter) Micronodules < 3mm
(diameter)
Darkly Pigmented
Affects Older Adults Often in Children
Morphology
No known Genetic Familial
component
Majority of Hyperplastic Adrenals arise
from 2° influences and (1° is uncommon )
Morphology (Depen d on Cause of Hypercorticolism)
Bilateral Cortical Atrophy (Iatrogenic, Exogenous)
(Due to Suppression of Endogen ous ACTH)
Diffuse Hyperplasia (60-70% cases of End ogenous )
(Diffusely Thickened Yellow Cortex due to ↑ Lipid Rich
cells)(Both Glands Enlarged 25-40g)
Nodular Hyperplasia (Bilateral, Scattered Yellow
Pituitary in Cushing Syndrome Cortices Nodules 0.5-2 cm)(Both Glands 30 -50g)
Crooke Hyaline Change (arrows) Primary Adrenocortical Neoplasms
(Benign – Adenoma, Malignant – Carcinoma)(Cortisol
Normal Granular Basophilic ACTH-producing cells are secreting tumours cannot be differentiated grossly from
replaced by homogenously light basophilic material non-functioning tumours)(W omen 30 -50 y/o ↑)

Changes resulting from ↑ Glucocorticoids

(Endogenous, E xogenous )

Result from accu mulation of Intermediate Keratin

Adrenal Gland
Filaments in cytoplasm (Cushing Syndrome)
Well-circums cribed Adrenal Cortex Adenoma
Adenoma, Bright Yellow Zona Fasciculata like cells
Capsule (left)
Mild Pleomorphism

Tumour Mass Cut Sections

Larger, Unencapsulated Irregular, Solid
Weight 800g Grayish → Yellow
No remaining Adrenal Areas of Haemorrhages,
Gland is identified Necrosis

Adrenal Cortical Carcinoma

Tumour Cells Arranged in Broad Trabeculae, Solid Nests
Anastomosing architecture, Rich Sinusoidal Network
Mild Pleomorphic
Round Nu cleus
Abundant Clear → Eosinophilic Distinct Cytoplasm
Mitosis is seen
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Hyperaldosteronism

Definition Morphology
Uncommon syndrome
Characterized by
Chronic Exce ss of Aldosterone Secretion
Na+ Retention, K+ Excretion
Hypertension, Hypokalaemia

Types
Primary (1°) Secondary (2°)
Autonomous overprodu ction Anything that cause Kidney Conn Syndrome (Aldosterone Produ cing Adenoma)
of Aldosterone to perceive Almost always Single, Small (< 2cm diameter)
↓ ↓ Intravascular Volume Well-circums cribed lesion often buried within gland, no visible enlargement
Suppressed RAAS (Activation of RAAS) Bright Yellow is composed of Lipid Laden Cortical Cells
↓
↓ Adenoma does not suppress ACTH secretion
↓ Plasma Renin Activity Aldosterone Release (Cortex of Adjacent Adrenal Tissue, Opposite Glands are Not Atrophic)
↓ Renin ↑ Renin Rarely Carcinoma may be responsible

Causes of Primary (1°) Hyperaldosteronism

Conn Syndrome (Aldosterone Produ cing Adenoma)

Proliferating Cellular Mass is Encapsulated
Cells are Uniform in Size, Shape
Resemble Mature Cortical Cells
Spironolactone Bodies (Post treatment with Anti-HPT drugs)
(Eosinophilic La minated Cytoplasmic Inclusion s)

Causes of Secondary (2°) Hyperaldosteronism

↓ Renal Perfusion (Arteriolar Nephrosclerosis, Renal Artery Stenosis)
Arterial Hypovolaemia, Edema (CHF, Cirrhosis, Nephrotic Syndrome)
Pregnancy (Esterogen induced ↑ in Plasma Renin Substrate)
Bilateral Idiopathic Hyperplasia
Diffuse, Focal Hyperplasia of cells resembling Zona Glomerulosa
Hyperplasia is Wedge Shaped extending from Periphery toward Centre of gland
Microscopic – Diffuse or Nodular Proliferation of Adrenal Cortical Cells

Adrenal Glands
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Adrenogenital Syndrome

Definition Consequence s of 21-Hydroxylase Deficiency

Disorder of Sexual Differentiation
Such as – Virilization, Feminization
Caused by Primary Adrenal Diseases or Gonadal Disorders
Adrenal Cortex secretes 2 compounds
• Dehydroepiandrosterone
• Androstenedione
Produced by Zona Reticularis
Converted to Testosterone (Peripheral Tissues)
Under the influence of ACTH secretion
Excess secretion can be a ‘pure’ syndrome or compone nt of Cushing Syndrome
Adrenal causes of Androgen excess
• Adrenocortical Neoplasms (Adrenocortical Carcinomas)
• Congenital Adrenal Hyperplasia (CAH)

Congenital Adrenal Hyperplasia (CAH)

Autosomal Recessive
Inherited metabolic errors
Characterized by
• Deficiency of a particular enzyme
• Total Lack of a particular enzyme
Involved in Biosynthesis of Cortical Steroids (particularly Cortisol) 21-Hydroxylase Deficiency
Steroid Synthesis is channelled into other pathways Defective conversion
↑ Androgen production, Virilization Progesterone → 11-Deoxycorticosterone (by 21-Hydroxylase)
Cortisol deficiency stimulates ACTH secretion Account for over 90% of cases of Congenital Adrenal Hyperplasia Syndrome
With resultant Adrenal Hyperplasia Deficiency varies from Mild Deficiency to Total Lack of enyzme
Certain enzyme defect may impair Aldosterone secretion (depend on nature of its mutation)
(adding salt wasting to virilisation) 3 Distinctive Syndromes
Other enzyme deficiencies may be incompatible with life or rarely may involve Non-Classic
Simple Virilizing
only the Aldosterone pathway without involving Cortisol synthesis Salt Wasting (Classic) Adrenogenitalism
Adrenogenitalism
Spectrum of Syndromes Adrenogenitalism (Late onset
without Salt Wasting
Very Mild → Total Lack of particular Enzymes Adrenal Virilism)
Total lack of Less than total lack of Very Mild Defect in
21-Hydroxylase 21-Hydroxylase 21-Hydroxylase
Progesterone Less severe deficiencies Very Mild Deficiencies
↓ of minerolocorticoid
Deoxycorticosterone but sufficient for Salt
↓
Mineralocorticoid Reabsorption
Concomittant block Lowered Glucocorticoid
deoxycortisol synthesis ACTH ↑
No synthesis of ↓ Mineralocorticoid Very Mild ↓ Steroid
Mineralocorticoids (Mild) Hormones
Deficient in Cortisol ↓ Cortisol (Mild) Mildly ↑ Testosterone
ACTH ↑ ↑ Androgen (Bioche mically)
Excess in Androgens
Hyponatremia Simple Virilization Very Mild
Hyperkalemia without salt wasting Androgen Excess
Virilization
Cardiovascular collapse
Possible Death
Girl – Easily recognized Ambiguous genitalia Genitalia normal at
at birth or in utero Signs of Masculinization birth
Boys – Difficult in Females to Asymptomatic except
Oligomenorrhaea, for mild symptoms of
Mild Clitoral Enlargement Hirsutism Androgen Excess in
↓
Puberty/ Childhood
Complete Labioscrotal
Fusion Male – Enlargement of (Hirsutism)
↓ External Genitalia,
Marked Clitoral Enlargment evidence of Precocious
(Enclosing Urethra
Puberty in prepubertial
resembled Penis)
patients, Oligospermia
in older males
Salt Losing Crisis
(soon after birth)
(5 – 15/7)
Electrolytes, Fluid
maintained by Maternal
Kidneys

Can be Life Threatening

Adrenals are Bilaterally Hyperplastic in all cases. Sometimes expanding up to
10-15X normal (d ue to sustained ↑ ACTH)
Adrenal Cortex is Thickened, Nodular
Widened Brown Cortex
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Adrenocortical Insufficiency Adrenocortical Ne oplasms

Classification Definition
Primary Secondary Functional Adenomas are most commonly associated with
Primary Hypoadrenalism ↓ Stimulation of Adrenals • Hyperaldosteronism
Acute Chronic owing to ↓ ACTH • Cushing Syndrome
Adrenal Crisis Chronic Insu fficien cy Virilizing Neoplasm ↑ Likely to be Carcinoma
(Addison Disease) Functional, Non-Functional can be determined based on Clinical, Bioche mically
(Not on Morphologic Features)
Acute Primary Insufficiency (Adrenal Crisis) • Adenoma
Sudden ↑ Demand for Steroid • Carcinoma
(precipitated by any form of stress that requires an immediate ↑ in Steroid
Output from glands in patient with Chronic Adrenocortical Insufficiency) Adenoma
Rapid Withdrawal of Steroids in patients maintained on Exogenous Steroid
(due to inability of Atrophic Glands to produce Steroid Hormones)
Massive Adrenal Haemorrhage with Destruction of Adrenal Cortex
(as occurs in Newborns with prolonged, difficult delivery – Trauma, Hypoxia)
Patients with DIC
Waterhouse-Friderichsen Syndrome
Waterhouse-Friderichsen Syndrome (Un common but Catastrophic syndrome )
Overwhelming Bacterial Infection
Adrenocortical Ne oplasm (Adenoma)
(classically – Neisseria meningitidis septicemia)
Well-Circums cribed
(occasionally – pseudomonas, pneu mococci, H. In fluenzae, staphylococci)
Nodular Lesion up to 2.5 cm in diameter that Expands the Gland
Rapidly progressing Hypotension leading to Shock
Yellow → Yellow-Brown (due to Lipid within Tumour Cells)
DIC with widespread Purpura of Skin
Most are clinically silent
Rapidly Developing Adrenocortical Insufficiency with
Massive Bilateral Adrenal Hemorrhage

Waterhouse-Friderichsen Syndrome
Can occur at any age (Children ↑)
Adrenocortical Ne oplasm (Adenoma)
Direct Bacterial Seeding of Small Vessels in Adrenal
Compose d of Cells similar to Normal Adrenal Cortex
Development of Endotoxin -Indu ced Vasculitis, DIVC
Adrenals converted to Sacs of Blood Clots (obscuring all underlying detail)
Carcinoma
Histology – Haemorrhages starts within Medulla expanding into Cortex
Rare, occur at any age
Death can follow within Hours → Few Days (unless appropriate treatment)
↑ Likely to be Functional than Adenomas
Often associated with
Primary Chronic Insufficiency (Addison Disease)
Uncommon • Virilism
Resulting from Progressive Destruction of Adrenal Cortex • Features of Hyperadrenalism
Generally, Clinical Manifestation appear when
at least 90% Adrenal Cortex compromised
90% Caused by
Autoimmune Adrenalitis (most common – developed countries)
Infection (Tu berculosis)(common – developing countries)
Acquired Immune Defi ciency Syndrome (AIDS)
Metastatic Cancers
Atrophy of Adrenal Gland
↓ Aldosterone
↓ Cortisol
Hyponatraemia (No Aldosterone)
Hyperpigmentation
(↑ ACTH but nowhere to go → Stimulate Melanocytes → Skin Adrenocortical Ne oplasm (Carcinoma)
Hyperpigmentation especially sun exposed areas, pressure points) Large
Hyperkalemia, Hypotension Invasive
Hypoglycaemia (due to ↓ Cortisol – Impaired Gluconeogenesis) Exceeding 20cm in Diameter
Variegated areas of Necrosis, Haemorrhage
Secondary Adrenocortical Insufficiency Cystic Change
Disorder of Hypothalamus, Pituitary (Smaller, Better Circumscribed Lesions are difficult to differentiate f rom adenoma)
(Metastatic Cancer, Infection, Infarction, Irradiation) Tendency to Invade
↓ ACTH Output → Syndrome of Hypoadrenalism • Adrenal Vein (common)
Prolonged Exogenous Steroid Administration • Inferior Vena Cava (IVC) (common)
(Suppress Adrenal Function) • Lymphatics
Hyperpigmentation is lacking Metastasis to Regional, Periaortic Nodes are common
(Melanotrophic Hormone Levels ↓) Distant Metastasis – Lung, other Viscera (Bone is Unusual Site)
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Adrenal Medulla

Definition Neuroblastoma Blast = Immature (Kids)

Most common E xtracranial Solid Tumour of Childhood
Most common d uring 1st 5 years of life
Site
• Abdomen (most common )
o Adrenal Medulla
o Retroperitoneal Sympathetic Ganglia
• Sympathetic Nervous System (occur anywhere)
Neuroblastoma
Most common Adrenal Medulla Tumour in Kids

Neuroblastoma
Brown Discoloration (Foci of Old Haemorrhage)
Sharply demarcated with a Fibrous Pseudocapsule
Pheochromocytomas P=Parents Infiltrative Invading Kidneys, Renal Vein, Vena Cava
Uncommon Neoplasm Soft Grey-Tan Brain Like Tissue
Pheochromocytoma Areas of Necrosis, Cystic Changes, Haemorrhage (Large Tumours)
Most common tu mour in Adrenal Medulla in Adults Size range Minute Nodules → Masses (> 1kg)
Chromaffin Cells secrete
• Epinephrine
• Norepinephrine
Give rise to Surgically Correctable Hypertension
(Hypertension becomes fatal in unrecognized pheochromocytoma )
May cause Cushing Syndrome or other endocrinopathy
(when produce other steroids, peptides)
5 P’s (Pain, Pressure, Palpitations, Perspiration, Pallor)
(Sympathetic Over Expression)
Rule of 10’s Neuroblastoma
10% Malignant (90% Benign) Tumour variably Mature to
Neuroblastoma
10% Bilateral (90% Unilateral)
Small, Blue, Round Cell Tumour • Ganglio-Neuroblastoma
10% Extra-Adrenal (90% Adrenal)
Arrange in Solid Sheets (Ganglion Cells Mixed with
10% Kids (90% Adults) Mitosis, Nuclear Breakdown, Primitive Neuroblasts)
10% Familial (90% Non-Familial) Pleomorphism • Ganglioneuroma
Associated with Faint Pink Fibrillary Material (No or Minimal Neuroblasts with
• MEN2A (Background) Mature Ganglion Cells in
• MEN2B Rosettes (Tumour Cells surroundi ng background of Schwann Cells,
• Other Familial Syndromes a central space filled with neuropil) Fibroblasts with their processes)
Clinical
Young Childre n <2 y/o Older Children
Abdominal Masses Metastasis
Fever Bone, Liver, Lung, Bone Marrow
Weight ↓
Tumour Produce Catecholamines (90%)
Hypertension (↓ Frequent)
Course – Extremely Variable
Pheochromocytoma (Adrenal Medulla) Prognosis affected by Clinical, Histologic, Molecular, Biochemical Factors
Surrounded by a Narrow Rim of Outstreched Yellow Cortical Tissue Indicators - Age, Stage of Tumour
Lobular pattern (richly vascularised fibrous trabeculae pass through tumour) Excellent Prognosis – Infants < 1 y/o (regardless of stage)
Yellow-Tan
Haemorrhage, Necrotic, Cystic (Larger Lesions) MENs
Range (Small Circumscribed lesion confined to Adrenal Gland → Large Group of Genetically Inherited Disease
Haemorrhagic Mass weighing in kg) Result from Proliferative Lesions (Hyperplasia, Adenoma, Carcinoma)
MEN Rule
Occur at younger age than in sporadic cancers
Arise in Multiple Endocrine Organs
• Metachronously (Different Time)
• Synchronously (Same Time)
If occur in One Organ – often Multifocal
Preceded by Asymptomatic Stage of Endocrine Hyperplasia (progress to cancer)
↑ Aggressive, Tend to Recur
MEN Syndromes
MEN 1 MEN 2A MEN 2B
Pheochromocytoma (Adrenal Medulla) Pituitary Adenoma
Parathyroid Hyperplasia+++ Hyperplasia+
Polygonal → Spindle Shaped Chromaffin Cells
Adenoma+
Zellballen (small nests, alveoli) Pancreatic Islet Hyperplasia++
Richly Vascular Adenoma++
Carcinoma+++
Round → Ovoid Nu clei (Chromatin Stipled Salt, Pepper)
Adrenal Cortical Hyperplas ia Pheochromocytoma++ Pheochromocytoma+++
Moderate → Abundant Finely Granular Cytoplasm Thyroid C-Cell Hyperp lasia+++ C-Cell Hyperp lasia+++
Uncommonly the dominant cell type is Spindle or Small Cell Medullary Carcin oma+++ Medullary Carcin oma+++
No single histologic critera that can reliably predict clinical behaviour Extraendocrine Mucosal
Changes Ganglioneuroma
Definitive diagnosis for malignancy is based on presence of Metastasis Marfanoid Habitu s
Lab Diagnosis – Demo ↑ Urinary Excretion of Free Catecholamines Mutant Gene Locus MEN 1 RET RET
and metabolites (Vanillymanelic acid (VMA), Metanephrines)