Endocrine System II (a) Flashcards
Adrenocortical Hyperfunction syndrome (Hyperadrenalism) examples
- Cushing Syndrome
- Hyperaldosteronism
- Adreno-Genital (or Virilising) Syndromes
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
causes of Cushing Disease
- ACTH-producing Micro-adenoma
- ACTH-producing Macro-adenoma
- Corticotroph Cell Hyperplasia
patho of Cushing disease
Elevated ACTH-levels –> Bilateral Nodular Cortical Hyperplasia –> Hypercortisolism (↑ cortisol)
Adreno-Cortical Hyperplasia is associated w/?
ACTH- producing Pituitary Adenoma
(Cushing disease)
Causes of Ectopic ACTH-secretion
Non-Pituitary tumours:
1) SCLC- small cell lung cancer
2) Carcinoid, Medullary Thyroid Carcinoma
Epi of Ectopic ACTH-secretion
10% of Cushing Syndrome cases
patho of Ectopic ACTH- secretion
Elevated ACTH-levels -> Bilateral Nodular cell Hyperplasia–> Hypercortisolism
Epi of Primary Adrenal Neoplasms (Adenoma or Carcinoma) or Primary Cortical Hyperplasia
(Macro-/ or Micro-nodular)
15%-20% of endogenous
Cushing Syndrome cases
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
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
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)
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
Patho of Primary Hyperaldosteronism
Primary autonomous over-production
of Aldosterone –> Suppression of Renin-Angiotensin
system –>Decreased plasma Renin activity
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!!!
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)
patho of Secondary Hyperaldosteronism
Activation of Renin-Angiotensin system (increased levels of plasma Renin) –> Aldosterone release
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
Managment of Aldosterone-producing Adenomas
* Conn Syn.
Surgical excision
Management of Bilateral Hyperplasia
*Caused by Secondary hyperaldostrenosim
Aldosterone antagonist
(e.g. Spironolactone)
* Becasuse Hypokalemia
causes of Adreno-Genital Syndromes
* Virilisation syn.
Excess of Androgens caused by:
1) Primary gonadal disorders:
Adrenocortical Neoplasms (CAs > Adenomas)
Congenital Adrenal Hyperplasia (CAH)
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
———– :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
- Primary Acute Adrenocortical Insufficiency
(Adrenal Crisis) - Primary Chronic Adrenocortical Insufficiency
(Addison Disease) - 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
