Endocrine System II (a) Flashcards by Elyaa Saleh

Adrenocortical Hyperfunction syndrome (Hyperadrenalism) examples

Cushing Syndrome
Hyperaldosteronism
Adreno-Genital (or Virilising) Syndromes

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causes of Hypercortisolism & Cushing Syndrome

* increase in Cortisol levels (hypercortisolism)

1) Administration of Exogenous glucocoticoids (↓ ACTH)
2) Primary adrenal carcinomas, adenomas or hyperplasia (↓ ACTH)
3) ACTH-secreting pituitary adenoma (Cushing disease)
4) Non-Pituitary Neoplasms –> Ectopic secretion of ACTH

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causes of Cushing Disease

ACTH-producing Micro-adenoma
ACTH-producing Macro-adenoma
Corticotroph Cell Hyperplasia

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patho of Cushing disease

Elevated ACTH-levels –> Bilateral Nodular Cortical Hyperplasia –> Hypercortisolism (↑ cortisol)

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Adreno-Cortical Hyperplasia is associated w/?

ACTH- producing Pituitary Adenoma
(Cushing disease)

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Causes of Ectopic ACTH-secretion

Non-Pituitary tumours:
1) SCLC- small cell lung cancer
2) Carcinoid, Medullary Thyroid Carcinoma

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Epi of Ectopic ACTH-secretion

10% of Cushing Syndrome cases

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patho of Ectopic ACTH- secretion

Elevated ACTH-levels -> Bilateral Nodular cell Hyperplasia–> Hypercortisolism

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Epi of Primary Adrenal Neoplasms (Adenoma or Carcinoma) or Primary Cortical Hyperplasia
(Macro-/ or Micro-nodular)

15%-20% of endogenous
Cushing Syndrome cases

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Lab findings of Primary Adrenal Neoplasms (Adenoma or Carcinoma) or Primary Cortical Hyperplasia (Macro-/ or Micro-nodular)

*Cushing’s Syn.

↑ serum Cortisol-levels
↓ serum ACTH-levels

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Morphology:
Crooked hyaline changes: Accumulation of intermediate keratin filaments in form of homogeneous lightly basophilic material, in cytoplasm of ACTH-producing cells

features of?

Cushing’s Syn. in the pituitary Gland

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CF of Cushing’s Syn

1) Truncal obesity
2) “Moon facies”
3) “Buffalo hump”
4) Thinned and easily bruised skin
5) Cutaneous striae in the abdominal region
6) Proximal limb weakness
7) Osteoperosis, with increased susceptibility to bone fractures
8) Hyperglycaemia, glucosuria and polydipsia
(mimicking Diabetes Mellitus)
9) Increased risk for a variety of infections (due to suppressed immune response) - Immunosupression
10) Hirsutism
11) Menstrual abnormalities
12) Mental disturbances (mood swings, depression, frank psychosis)

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causes of Primary Hyperaldosteronism

1) Bilateral idiopathic Hyperaldosteronism; Bilateral Nodular Hyperplasia of Adrenals; 60% of cases
2) Aldosterone-producing Adenoma (Conn Syndrome); 35% of cases
3) Familial Hyperaldosteronism, due to genetic defect with over-activity of Aldosterone synthase gene,
CYP11B2

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Patho of Primary Hyperaldosteronism

Primary autonomous over-production
of Aldosterone –> Suppression of Renin-Angiotensin
system –>Decreased plasma Renin activity

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Macroscopic Features:
* Solitary, small, well-circumscribed lesions
* Cut surface: Bright yellow colour

Microscopic Findings:
* Uniform cells, Admixture of fasciculata and glomerulosa-type cells
* nuclear & cellular pleomorphism
* Eosinophilic, laminated cytoplasmic inclusions (Spironolactone bodies), after treatment with Spironolactone

Syndrome?

Aldosterone-producing Adenomas - Conns Syndrome

* Celluar pleomorphism means that it is not malignant!!!

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casues of Secondary Hyperaldosteronism

Decreased renal perfusion (Arteriolar Nephrosclerosis, Renal Artery Stenosis)
Arterial hypovolaemia and oedema (CHF, Cirrhosis, Nephrotic Syndrome)
Pregnancy (Oestrogen induced Renin-increase)

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patho of Secondary Hyperaldosteronism

Activation of Renin-Angiotensin system (increased levels of plasma Renin) –> Aldosterone release

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CF of secondary Hyperaldosteronism

1) Secondary hypertension –> Left ventricular
hypertrophy and increased risk for stroke and
myocardial infarction
2) Hypokalaemia, due to renal potassium wasting –> Muscle weakness, paraesthesias, visual
disturbances, and sometimes tetany

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Managment of Aldosterone-producing Adenomas

* Conn Syn.

Surgical excision

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Management of Bilateral Hyperplasia

*Caused by Secondary hyperaldostrenosim

Aldosterone antagonist
(e.g. Spironolactone)

* Becasuse Hypokalemia

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causes of Adreno-Genital Syndromes

* Virilisation syn.

Excess of Androgens caused by:
1) Primary gonadal disorders:
 Adrenocortical Neoplasms (CAs > Adenomas)
 Congenital Adrenal Hyperplasia (CAH)

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patho of Congenital Adrenal Hyperplasia (CAH)

Group of autosomal recessive disorders;
Hereditary defect in an enzyme involved in
adrenal steroid biosynthesis, commonly
Cortisol –> Decreased Cortisol levels –>
Increased ACTH secretion –> Adrenal
Hyperplasia –> Increased production of
Cortisol precursor Steroids –> Synthesis of
Androgens –> Virilising Syndrome

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———– :Most common enzymatic defect <> 21-Hydroxylase deficiency; mutation in the CYP21A2 gene

Congenital Adrenal Hyperplasia (CAH)

Morphology :
* Bilateral Hyperplastic Adrenals
* Thickened, nodular and brown Adrenal Cortex
* Mainly, compact, eosinophilic, lipid depleted cells, intermixed with a variable number of lipid-laden clear cells

Syndrome?

Congenital Adrenal Hyperplasia (CAH)

CF of Congenital Adrenal Hyperplasia (CAH)

21-Hydroxylase deficiency --> Androgen excess: 1) **Clitoral hypertrophy and pseudohermaphroditism** (female infants) * **Oligomenorrhea, hirsutism and acne** (postpubertal girls) * **Enlargement of external genitalia** (prepubertal males) * **Oligospermia** (older male patients)

# *Congenital Adrenal Hyperplasia (CAH) 1/3 of patients with 21-Hydroxylase deficiency --> Mineral-Corticoid deficiency --> ----------

Salt wasting

# * Congenital Adrenal Hyperplasia (CAH) Cortisol deficiency in CAH patients have a Risk for the development of ?

Acute Adrenal Insufficiency

causes of Adrenal Insufficieny

1) Primary Adrenal Disease (**Primary Hypoadrenalism**) 2) Decreased stimulation of Adrenals, due to a deficiency of ACTH (**Secondary Hypoadrenalism**)

Adrenal Insufficiency Examples

1. Primary Acute Adrenocortical Insufficiency (Adrenal Crisis) 2. Primary Chronic Adrenocortical Insufficiency (Addison Disease) 3. Secondary Adrenocortical Insufficiency

causes of Acute Adreno-Cortical Insufficiency (Adrenal Crisis)

1) Massive Adrenal haemorrhage: * **Waterhouse-Friderichsen Syndrome** (overwhelming sepsis caused by **Neisseria meningitidis**) * Patients under anticoagulant therapy * Disseminated Intravascular Coagulation (**DIC**) 2) Rapid withdrawal of steroids or failure to corticosteroid therapy 3) Failure to increase steroid doses in response to an acute stress

Causes of primary Chronic Adreno-Cortical Insufficiency (Mb. Addison)

1) **Autoimmune Adrenalitis** (immune system attacks the adrenals) 2) Primarily, **metastatic carcinomas** from the lung and breast 3) Infections and immune deficiency states: **Tuberculosis**, Patients with **AIDS**; Adrenal insufficiency from infectious (e.g. **CMV**) and non-infectious complications (e.g. **Kaposi Sarcoma**) of their disease | * CMV : cytomegalovirus

Causes & Pathogenesis of Secondary Adreno-Cortical Insufficiency

**Disorders of Hypothalamus or Pituitary** (metastatic cancer, infection, infarction, irradiation, etc.) -> **Decreased production of ACTH --> Hypo-Adrenalism**

LAB findings of Secondary Adreno-Cortical Insufficiency

* Low serum ACTH * Marked rise in plasma Cortisol levels, caused by exogenous ACTH administration

Morphology: * Irregularly **shrunken glands** * Scattered residual cortical cells, in a collapsed network of connective tissue * Variable **lymphoid infiltrates** Syndrome?

Primary Autoimmune Adrenalitis

Morphology:  Small and **flattened organs**  **Uniform thin rim of yellow cortex**, around a **centrally located** intact medulla  **Atrophy of cortical cells**, with loss of cytoplasmic lipid Syndrome?

Secondary Hypo-Adrenalism

CF of Adrenal Insufficiency

1) **Progressive weakness and easy fatigability** 2) GI disorders (anorexia, nausea, vomiting, weight loss, diarrhoea) 3) **Hyperpigmentation of the skin** and mucosal surfaces (**Primary Adrenal disease, Addison's**) 4) **Hyperkalaemia** (d/t reduced aldosterone), **Hyponatraemia** 5) **Hypotension** (**Primary Adrenal insufficiency**) 6) **Deficient Cortisol and Androgen output , and near-normal Aldosterone synthesis (Secondary Hypo-Adrenalism**) 7) **Stress conditions** (e.g. trauma, infection) --> **Acute Adrenal Crisis** (hypotension, coma, vascular collapse)

# * Macroscopic Features: * Size: 1-2cm * Cut surface: **Yellow to yellow-brown** Microscopic Findings: * **Small cells, similar to** these of the normal **adrenal cortex** * Small nuclei, with **some degree of pleomorphism** (**endocrine atypia**) * **Eosinophilic to vacuolated cytoplasm** * Admixture of clear and compact cells * **Extensive fibrosis** of the stroma Syndrome?

Adreno-Cortical **Adenomas** | * aka **“Adrenal Incidentalomas”**

Adreno-Cortical Carcinomas Inherited causes

i. Li-Fraumeni Syndrome ii.Beckwith-Wiedemann Syndrome

Macroscopic Features: * **Large, invasive lesions** * Cut surface: Poorly demarcated masses, with **necrosis, haemorrhage** and cystic changes * **Alveolar pattern of growth** Microscopic Findings: * **Well-differentiated cells** (similar to those of Adenomas) or bizarre pleomorphic cells * Few intranuclear **“pseudo-inclusions”** Syndrome?

Adreno-Cortical Carcinomas

Adreno-cortical Carcinomas are Associated w/ **----------**

**Virilisation**

**-------- cells -->** Synthesis of Catecholamines (mainly Epinephrine), in response to signals from preganglionic nerve fibers in the Sympathetic Nervous System

Chromaffin cells | * Found in the adrenal Medulla

What Neoplasms synthesize and release Catecholamines ? | * Catecholamines are released by Chromaffin cells

Pheochromocytoma

**“rule of 10s”** of Pheochromocytoma

* 10% of Pheochromocytomas ---> **Extra-Adrenal**; occurrence in the organ of Zuckerkandl and the Carotid body (named Paragangliomas) * 10% of Adrenal Pheochromocytomas -> **Bilateral** * 10% of Adrenal Pheochromocytomas -> **Malignant** * 10% of Adrenal Pheochromocytomas -> **Not associated with Hypertension**

Familial cases: 25% of patients with Pheochromocytomas and Paragangliomas --> have Germline mutations in one of the 4 genes, what are they?

* **RET --> MEN Type 2 syndrome** * NF1 --> Neurofibromatosis Type 1 syndrome * VHL --> Von Hippel Lindau disease * SDHB, SDHC and SDHD

Macroscopic Features: a. Small, circumscribed lesions that compress the adjacent adrenal or b. Large, haemorrhagic, necrotic and cystic masses that **destroy the adrenal gland** Microscopic Findings: * **Polygonal to spindle-shaped Chromaffin cells** and the Sustentacular cells --> Formation of **“Zellballen”**, with a rich vascular network * Finely granular cytoplasm * Quite pleomorphic nuclei* * Capsular and vascular invasion Syndrome?

Pheochromocytoma

# * Stain/ tests used in the detection of Pheochromocytoma

**Chromogranin A** (Tumour marker) , **S-100** (stain)

CF of Pheochromocytoma

* **Hypertension** (abrupt elevation of BP, together with tachycardia, palpitations, headache, sweating and tremor) * **Abdominal and/or chest pain** * **Nausea and vomiting**

Complications of Pheochromocytoma

Increased risk for myocardial ischaemia, heart failure, renal injury and stroke

Lab findings of Pheochromocytoma

Increased urinary excretion of free **Catecholamines** and their metabolites

Epi of Neuroblasmtoma

Most common extra-cranial solid tumour of **childhood**

loc of Adrenal Neuroblastomas

* **Adrenal Medulla (40%)** * Paravertebral region of the Abdomen (25%) * Posterior Mediastinum (15%)

Macroscopic Features: * Sharply demarcat., with **fibrous pseudocapsule** or Infiltrative tumour with **invasion** of adjacent structures (e.g. kidneys, renal vein, vena cava, etc.) * **Cut-Surface**: Soft, **gray-tan, brain-like tissue** Microscopic Findings: Small, **primitive appearing cells** with: * **Dark nuclei** * Scant cytoplasm * Poorly defined cell borders * Growth pattern --> Solid sheets * High mitotic index * **Karyorrhexis (irregular distribution of Chromattin cells)** * Pleomophism * Background: Faintly eosinophilic fibrillary material * ***Homer-Wright pseudo-rosettes** Syndrome?

Neuroblastoma of the Adrenal Medulla | * primitive appearing cells --> neuroblasts

# * Immunohistochemistry detection of Neuroblastoma of the Adrenal Medulla

Neuron Specific Enolase (NSE), Synaptophysin

# ** Micro of Ganglio-Neuroblastomas vs Ganglio-Neuromas

Ganglio-Neuroblastomas: - Ganglion cells, - Neuroblasts (Primitive appearing cells), - **"Schwannian stroma"** Ganglion-Neuromas: - Ganglion cells , - **"Schwannian stroma"**

Factors that influence the prognosis of Neuroblastoma

1) **Age** : children <18 months (better prognosis than older ones) 2) **Stage** of the tumour 3) **Morphology: “Schwannian stroma”** andGangliocytic differentiation --> Favourable histologic pattern (Ganglio-neuromas/Ganglio-neuroblastoma) 4) **NMYC Amplification**: The greater the number of copies, the worse the prognosis; Most important genetic abnormality; **Independent factor for rendering a tumour as “high” grade**, irrespective of stage or age, irrespective of stage or age 5) **Disseminated Neuroblastomas in neonates** --> Multiple cutaneous metastases (characteristic deep blue discolouration of the skin, known as **“blueberry muffin baby”**)

Lab findings of Neuroblastomas

* Elevated blood levels of Catecholamines * Elevated urine levels of Catecholamine metabolites (Vanillyl-Mandelic Acid **[VMA]** and Homo-Vanillic Acid **[HVA]**)

# ** What tumour causes characteristic deep blue discoloration of the skin, known as **“blueberry muffin baby”**

Neuroblastoma of the Adrenal Medulla