Adrenal Flashcards
Adrenal structure
Zona Glomerulosa
* Mineralcorticoids
* Aldosterone
* Conn’s
Zona Fasiculata
* Glucocorticoids
* Cortisol
* Corticosterone
* Cortisone
* Cushings
Zona Reticularis
* Androgens
* Dehydroepiandrosterone
* Congenital adrenal hyperplasia
Adrenal Medulla
* Stress hormones
* Epinephrine
* Norepinephrine
Hyperaldosteronism
(Conn’s Syndrome)
- Adrenal glands secrete too much aldosterone
- Urinary loss of potassium and hypokalemia
- Sodium retention and hypertension
- Sodium retention causes volume overload –> suppresses the renin-angiotensin system –> reduces plasma renin activity –> volume overload causes polyuria, polydipsia, nocturia, hypertension, alkalosis and hypernatremia
Primary hyperaldosteronism:
* Due to adrenal pathology (most common are adenoma and cortical hyperplasia), idiopathic and rarely carcinoma; also called Conn syndrome
Secondary hyperaldosteronism:
* Due to increased levels of plasma renin from non-adrenal pathology, including congestive heart failure, pregnancy (due to estrogen), decreased renal perfusion (renal arterial stenosis, nephrosclerosis), hypoalbuminemia, ovarian tumor and hyperthyroidism
Tertiary hyperaldosteronism (Bartter syndrome):
* hypertrophy and hyperplasia of renal juxtaglomerular cells
* elevated plasma renin, angiotensin II and aldosterone
* hypokalemic alkalosis but no hypertension
* some cases are autosomal recessive
* glucocorticoid suppressible hyperaldosteronism -
Symptoms of Conn’s Syndrome:
* Hypertension (High Blood Pressure) –> typically systolic ≥ 160 mmHg or diastolic ≥ 100 mmHg.
* Hypokalemia (Low Potassium Levels) –> Muscle weakness, cramps, fatigue, arrhythmias (irregular heartbeats) and paralysis.
* Metabolic Alkalosis
* Polyuria and Polydipsia –> trying to excrete the excess fluid and maintain electrolyte balance.
* Headaches and Fatigue
Causes of Conn’s Syndrome:
Adrenal Adenoma (Aldosterone-Producing Tumor):
* A benign tumor of the adrenal gland that produces aldosterone in excess.
* Most common cause of Conn’s syndrome.
* Typically a single tumor on one of the adrenal glands.
Bilateral Adrenal Hyperplasia:
* Both adrenal glands become enlarged and produce too much aldosterone. This is less common than adrenal adenomas.
Diagnosis of Conn’s Syndrome:
Blood Tests:
* Elevated aldosterone levels in the blood.
* Low plasma renin activity (PRA)
* Hypokalemia (low potassium) is common.
* Aldosterone-to-Renin Ratio (ARR): A high ARR indicates excessive aldosterone production relative to renin, which is characteristic of Conn’s syndrome.
Imaging:
* CT scan or MRI of the adrenal glands
Confirmatory Testing:
* Salt-loading test: The patient is given salt orally, and aldosterone levels are measured. If aldosterone remains high despite the increased salt (which normally should suppress aldosterone production), it confirms the diagnosis.
* Fludrocortisone suppression test
* Adrenal Vein Sampling:
Treatment of Conn’s Syndrome:
* Surgical Treatment
* Aldosterone antagonists like spironolactone or eplerenone are commonly prescribed. These medications block the effects of aldosterone, helping to reduce blood pressure and correct potassium levels.
* Potassium supplements may also be required to correct hypokalemia.
Cushing’s
Cushing syndrome
Can be caused by excess cortisol from inside or outside the body. For example, it can be caused by taking corticosteroid medications or by tumors in the pituitary or adrenal glands.
Cushing disease
Caused by a benign tumor in the pituitary gland that produces too much adrenocorticotropic hormone (ACTH). ACTH signals the adrenal glands to produce cortisol.
Causes:
Pituitary Adenoma (Cushing’s Disease):
* Most common cause of Cushing’s syndrome is a benign tumor in the pituitary gland.
* Produces excess adrenocorticotropic hormone (ACTH), which stimulates the adrenal glands to produce too much cortisol.
Ectopic ACTH Syndrome:
* Some tumors outside of the pituitary (such as lung cancer) can secrete ACTH, leading to high cortisol levels.
Medications:
* The use of corticosteroid medications (like prednisone) over a long period can also lead to Cushing’s syndrome.
Symptoms:
* Weight gain, particularly around the abdomen, face (moon face), and upper back (buffalo hump)
* Thinning skin that bruises easily
* Purple or pink stretch marks on the abdomen, thighs, or arms
* Muscle weakness and thinning of the limbs
* High blood pressure (hypertension)
* Osteoporosis, leading to bone fractures
* Mood swings, anxiety, depression, or irritability
* Increased risk of infections due to suppressed immune function
* Irregular menstrual cycles in women and reduced fertility
* Excessive hair growth in women (hirsutism), and sometimes acne
* Glucose intolerance or diabetes-like symptoms (due to cortisol’s effect on insulin)
Diagnosis:
24-hour urinary free cortisol test:
* Measures cortisol levels in the urine.
Low-dose dexamethasone suppression test:
* Normally, dexamethasone will suppress the body’s natural production of cortisol.
* In cases of Cushing’s syndrome, cortisol levels remain high even after dexamethasone administration.
* Low-dose test: A small dose of dexamethasone (typically 1 mg) is taken orally, usually at night.
* High-dose test: A higher dose (typically 8 mg) is used if further investigation is needed after the low-dose test.
Normal response:
* Dexamethasone suppresses the secretion of ACTH from the pituitary gland
* Leading to a drop in cortisol production from the adrenal glands.
* Cortisol levels should fall in response to the dexamethasone.
Abnormal response (Cushing’s syndrome):
* Cortisol production does not decrease or only decreases minimally, even after dexamethasone administration.
* The response can vary depending on the underlying cause
Pituitary tumor (Cushing’s disease)
* ACTH levels may still be suppressed by high doses
* As adrenal gland still has some control
* But not by low doses.
Adrenal tumor
* Dexamethasone has little effect on cortisol production
* Adrenal tumor produces cortisol independently of ACTH regulation.
* If the cause is ectopic ACTH production (like from a lung tumor), dexamethasone will have little effect, because the ectopic tumor produces ACTH independently of normal feedback mechanisms.
Imaging tests (CT or MRI):
* To look for tumors in the adrenal glands or pituitary.
SUMMARY:
Primary hypercortisolism/Cushings syndrome/Adrenal Cushings:
* Cortisol not suppressed by low or high doses
* ACTH undetectable or low
Ectopic ACTH syndrome:
* Not suppressed by high or low doses
* ACTH elevated in hundreds
Cushing’s disease (Pituitary tumour):
* Cortisol not suppressed by low doses, but is suppressed by high doses
* ACTH normal to mildly elevated
Treatment:
The treatment depends on the underlying cause:
Surgery:
* If a tumor is the cause (like a pituitary tumor), surgical removal may be necessary.
* Medications: Drugs can help control cortisol production. These are typically used when surgery isn’t an option or as adjuncts to surgery.
* Radiation therapy: If surgery doesn’t completely remove the tumor, or if it’s not surgically accessible, radiation may be used to shrink the tumor.
Pigmented adrenal cortical hyperplasia
- Also called primary pigmented nodular adrenocortical disease
- Rare cause of ACTH independent Cushing syndrome
- May be familial, autosomal dominant
- Associated with Carney complex
- 2p16 abnormalities
- Sporadic and nonfamilial patients are usually infants or age < 30 years
Macro:
* Variably sized adrenal glands with multiple brown-black pigmented cortical nodules, 1 mm to 3 cm
* Atrophy of adjacent cortical tissue
* Nodules may extend into corticomedullary junction or periadrenal fat
Micro:
* Sharply circumscribed but unencapsulated nodules composed of large eosinophilic lipid poor cells similar to zona reticularis but often with enlarged pleomorphic nuclei, prominent nucleoli and prominent lipofuscin deposits
* Also lipid rich fasciculata-like cells
* May have focal necrosis, mitotic activity, trabecular growth pattern, myelolipomatous change and lymphocytic infiltrates
Congenital adrenal hyperplasia
- Various autosomal recessive syndromes due to enzyme deficiencies in biosynthesis of adrenal steroids, diverting production to other pathways and causing elevated ACTH levels and adrenocortical hyperplasia
- Usually children, rarely adults; no gender preference
- Symptoms depend on specific defect; include salt wasting, virilization, adrenogenital syndrome and hypertension
Specified enzyme deficiencies
21-hydroxylase deficiency:
* Causes 95% of cases
* block in production of aldosterone and cortisol –> less sodium, hypotension
* high plasma ACTH
* Increased testosterone –> causes virilizing syndrome, ambiguous genitals in females,c
* variable salt wasting syndrome
* Leydig cell hyperplastic nodules without Reinke crystalloids
11-beta hydroxylase deficiency:
* Second most common form (5%), incidence of 1 per 100,000 live births
* associated with increased androgens and deoxycorticosterone; causes virilization and hypertension
17-alpha hydroxylase deficiency:
* causes 1% of cases
* all patients have female external genitalia due to increased deoxycorticosterone
* hypertension
3 beta hydroxysteroid dehydrogenase deficiency:
* impaired synthesis of all steroid hormones
* adrenal gland is similar to normal fetus
* patients present in early infancy with adrenal insufficiency
* variable virilization in females
Acute Adrenal Insufficiency
- Acute adrenal insufficiency due to bilateral haemorrhages in cortex
- Due to gram negative septicemia
Clinical
* Bleeding (apoplexy) into adrenal glands
* Causes adrenal gland failure
* Shock
* Hypoglycaemia
* Acidosis
* Acute renal failure
* DIC
* Death in 15-30 hours
Causes:
* Septicemia –> Waterhouse-Friderichsen Syndrome
* Neisseria meningitidis –> main cause
* Staph aureus
* Group B streptococci
* Strep pneumoniae
* Pseudomonas aeruginosa
* TB
* Anticoagulant therapy
* Coagulation disorder
* Adrenal vein thrombosis in pregnancy
* Congenital adrenal hyperplasia
* Sudden steriod withdrawal in long term corticosteroid users
Addison disease
- Also called primary chronic adrenal insufficiency
- No symptoms until 90% of cortex is compromised
- More common in white women
**Causes: **
* autoimmune disorders
* infections (Histoplasma, Coccidiodes, tuberculosis)
* space occupying lesions (metastases, lymphomas),
* hemorrhage,
* amyloid, sarcoid or hemochromatosis
**Symptoms: **
* progressive weakness, easy fatigability,
* anorexia, weight loss,
* depression, irritability,
* menstrual abnormalities,
* GI disturbances
* hyperpigmentation (primary adrenal disease causes elevated ACTH, which stimulates melanocytes at sun exposed areas and pressure points)
* small heart (due to chronic hypovolemia) and hypotension
* infections may precipitate an acute crisis
Laboratory:
* elevated ACTH levels
* low cortisol levels that do not respond to exogenous ACTH (since adrenal gland is damaged),
* hyponatremia,
* hypoglycemia, hyperkalemia and occasionally hypercalcemia
Beckwith-Wiedemann syndrome
- Overgrowth syndrome present at birth with certain congenital anomalies and increased risk of pediatric cancer
- Adrenal hyperfunction / hyperplasia
Clinical:
* Macrosomia
* Macroglossia
* Visceromegaly
* Embryonal neoplasms; mainly Wilms tumor and hepatoblastoma
* Omphalocele / exomphalos
* Adrenocortical cytomegaly
* Renal abnormalities
* Neonatal hypoglycemia
Micro:
* Adrenal cytomegaly
* Adrenal cortical cells with bizarre, enlarged polyhedral cells with granular eosinophilic cytoplasm and large, hyperchromatic nuclei with pseudoinclusions
* Placental mesenchymal dysplasia
* Dilated and thick walled chorionic plate vessels with fibromuscular hyperplasia
* Hyperplasia of islets of Langerhans in the pancreas
* Cystic tubules in the medullary region of the kidney
* Hyperplasia of the interstitial cells in the ovary
Adrenal cortical adenoma
- Benign neoplasm arising from adrenal cortical cells
- May (15%) or may not (85%) be functional
- Usually unilateral, solitary
- Associated with MEN1, FAP, Carney complex
- Incidentaloma: small adenoma discovered incidentally during workup of other conditions
- Black (pigmented) adenoma: diffusely pigmented, brown-black ACA presumably due to lipofuscin
- Hypercortisolism: sometimes used synonymously for Cushing syndrome
- Aldosterone-producing –> Conn’s
- Sex hormone producing –> Rare
Micro:
* In comparison to surrounding adrenal gland, adenoma cells are larger with different cytoplasm, increased variation in nuclear size
* Distinct cell borders, cells have abundant foamy cytoplasm reminiscent of zona fasciculata
* Balloon cells: clusters of cells with enlarged lipid-rich cytoplasm (seen in Cushing syndrome)
* Low/No mitotic activity
* Intact reticulin framework
* Histologic variants: oncocytic, myxoid
IHC:
Usually positive:
* α-inhibin
* MelanA / Mart1,
* steroidogenic factor-1 (SF-1)
* Calretinin
Negative stains
EMA,
CEA,
S100,
chromogranin (stains adrenal medulla)
Spironolactone bodies
- Spironolactone bodies are inclusions that form in the adrenal gland of patients who have been treated with spironolactone.
- They are made up of aldosterone and phospholipid.
- They are round, acidophilic, and cytoplasmic
- They have a laminated appearance
- They are concentric whorls of smooth membranes
- They may be a compensatory attempt by the cell to produce more mineralocorticoid
- They may be a result of the duration of spironolactone administration or the total drug dosage
Adrenal cortical carcinoma
- Malignant epithelial tumor of adrenal cortex
- Adrenocortical carcinoma (ACC) is a rare endocrine tumor with high mortality
- Vast majority are sporadic but could present in different syndromic settings
- Heterogeneous group of tumors with prognosis dependent on patient age, clinical presentation, stage, histologic variant and molecular / genomic characteristics
Could occur in a wide variety of disorders,:
* Multiple endocrine neoplasia type 1 (MEN1),
* Lynch,
* Li-Fraumeni,
* Beckwith-Wiedemann,
* Adenomatous polyposis coli (APC)
* Neurofibromatosis type 1 (NF1) syndromes,
* Carney complex
* Congenital adrenal hyperplasia
Clinical:
Functional adrenal cortical carcinomas have the following symptoms related to hormone production:
* 50% cortisol excess (Cushing syndrome, rapid onset)
* 20% sex hormone secretion (mainly androgens causing hirsutism, virilization and menstrual irregularities)
* 8% aldosterone (hypertension, hypokalemia)
* 15 - 25% mixed hormone production
Nonfunctional adrenal cortical carcinomas could present in 2 ways:
* 80% create a mass effect (gastrointestinal symptoms, organ compression or back pain)
* mimic an infectious process (localized pain, fever due to cytokines from highly necrotic tumors)
* 20% discovered incidentally during unrelated imaging procedures
Scoring:
To determine benign vs malignant:
Weiss criteria: ≥ 3 for adrenal cortical carcinoma
1 Nuclear grade III or IV (Fuhrman)
2 > 5 mitotic figures/50 high power fields
3 Atypical mitotic figures
4 Clear or vacuolated cells ≤ 25% tumor
5 Diffuse architecture (> 33% of tumor)
6 Necrosis
7 Venous invasion (of smooth muscle walled vessels)
8 Sinusoidal invasion
9 Capsular invasion
one point each
* 0-2 –> benign
* 3 –> borderline
* 4-9 –> malignant
Prognosis:
Tumor stage is the best prognostic factor:
- Size of organ in confined tumor (rare presentation)
pT1 (≤ 5 cm), 5 year survival 82%
pT2 (> 5 cm), 5 year survival 58 - 61% - Invasion (majority of tumors):
pT3: local invasion, 5 year survival 47 - 56%
pT4: adjacent organs (kidney, diaphragm, pancreas, liver, spleen), 5 year survival 37%
Distant metastases at diagnosis (~40% of cases): 5 year survival 0 - 18%
Micro:
* Encapsulated tumor composed of variably sized nests, large sheets and trabeculae
* Invasion of thick fibrous capsule
* Lymphovascular invasion (venous or sinusoidal)
* Areas of necrosis, hemorrhage, degeneration are common
* Large cells with granular clear to eosinophilic cytoplasm, often pleomorphic
* Frequent intranuclear inclusions, mitoses, atypical mitoses
Grade defined by mitotic frequency:
* Low grade: ≤ 20 mitoses/50 high power fields
* High grade: > 20 mitoses/50 high power fields
Morphologic subtypes:
* Conventional (vast majority, 70 - 90% of cases)
* Oncocytic (> 90% oncocytic cells; second most common subtype)
* Myxoid (abundant extracellular mucin)
* Sarcomatoid (mesenchymal differentiation)
* Loss of continuity of the reticular fibers or basement membrane network (> 33% lesion)
Molecular:
* IGF2 overexpression is a major event in adrenal cortical carcinoma tumorigenesis
IHC:
* Steroidogenic factor 1 (SF1)
* calretinin
* inhibin
* MelanA / MART1
* synaptophysin
* neuron specific enolase (NSE),
* IGF2
* Reticulin to highlight disrupted network
Pheochromocytoma
- Paraganglioma of the adrenal medulla composed of chromaffin cells that produce catecholamines
Clinical:
* Classic triad of episodic headaches, sweating and tachycardia present in about 30%
* Other common features: palpitations, anxiety, postural hypotension and paroxysmal hypertension (normal in 10 - 30%)
* 10 - 30% present with adrenal incidentaloma and no symptoms (subclinical pheochromocytoma)
* Malignant in 10%
Related syndromes:
* Von Hippel-Lindau syndromes
* MEN2
* NF1
* Familial paraganglioma
Clinical and pathologic features of pheochromocytoma associated with malignancy:
Clinical features
* Younger age
* Secretion of norepinephrine
Gross features
* Tumor size
* Tumor weight
* Histologic features Periadrenal adipose tissue invasion
* Mitotic rate
* Atypical mitoses
* Necrosis
* Cellular spindling
* Marked nuclear pleomorphism
* Cellular monotony
* Large nests or diffuse growth
* High cellularity
* Capsular invasion
* Vascular invasion
* Hyperchromasia
Ancillary studies
* Higher Ki67
* SDHB, VHL, RET mutations
Micro:
* Nested (zellballen), trabecular or solid arrangement
* Nests outlined with sustentacular cells best visualized with S100 immunostain
* Cells: large, polygonal, uniform or extensively vacuolated
* Cytoplasm: abundant fine, granular red-purple cytoplasm
* Pigmented granules containing hemosiderin, melanin, neuromelanin and lipofuscin may be seen
* Nuclei: may be uniform or exhibit extensive variation in size, round to oval nuclei, nucleoli prominent
* Pheochromocytoma of the adrenal gland scaled score (PASS) and grading system for adrenal pheochromocytoma and paraganglioma (GAPP) can be used to assess for malignant potential
* Composite pheochromocytoma: pheochromocytoma with ganglioneuroma, ganglioneuroblastoma, neuroblastoma or peripheral nerve sheath tumors
IHC:
Chromogranin A
Synaptophysin
S100 expressed in nucleus and cytoplasm of sustentacular cells and some pheochromocytes throughout tumor
GATA3 diffuse nuclear expression in approximately 70%
Paraganglioma
- Nonepithelial, neural crest derived neuroendocrine neoplasms arising from the adrenal medulla (pheochromocytoma) and extra-adrenal paraganglia
- Composed of paraneuronal peptide hormone secreting neuroendocrine cells
- Histologically similar, regardless of location
2 categories:
* Parasympathetic: arises predominately in the head and neck
* Sympathetic: arises in the retroperitoneum, thorax and pelvis
