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Kutikov, A., P. L. Crispen, and R. G. Uzzo. "Pathophysiology, evaluation, and medical management of adrenal disorders." Campbell-Walsh Urology 12 (2020).

Kutikov, A., P. L. Crispen, and R. G. Uzzo. "Pathophysiology, evaluation, and medical management of adrenal disorders." Campbell-Walsh Urology 12 (2020).

Kutikov, A., P. L. Crispen, and R. G. Uzzo. "Pathophysiology, evaluation, and medical management of adrenal disorders." Campbell-Walsh Urology 12 (2020).

Kutikov, A., P. L. Crispen, and R. G. Uzzo. "Pathophysiology, evaluation, and medical management of adrenal disorders." Campbell-Walsh Urology 12 (2020).

How to Workup an Adrenal Mass

Identification

• Incidental diagnosis of adrenal mass > 1cm without presence of another malignancy
• 20% may be surgical candidates
• Size matters: if < 4cm, 2% are adrenal carcinomas, 4-6cm increases to 6%, 4cm recommended as cutoff for surgical intervention (93% sensitivity and 42% specificity)

Metabolic Workup

• > 10% adenomas are metabolically active
• Every patient should undergo metabolic workup at diagnosis - cortisol + metanephrines, aldosterone only if poorly controlled (refractory) hypertension
• Cortisol: assess with low dose dexamethasone suppression test - take 1mg between 11PM-12AM, check cortisol between 8-9AM the following day, cutoff between 1.8-5mg/dL
• Catecholamines: either use free fractionated plasma metanephrines (avoid stimulating agents, draw after 20 minutes supine) or 24hr urinary fractionated metanephrines (collect after discarding first morning void)
• Aldosterone: assess with aldosterone/renin ratio drawn 8-10AM, cutoff ARR > 20 and aldosterone level > 15
• Sex steroids: not recommended due to rarity of hypersecretion, only recommended if carcinoma is suspected or obvious signs of feminization/virilization - check DHEA, 17-ketosteroids, testosterone (virilization), 17B-estradiol (feminization)
• Only 2% spontaneously start producing hormones while on surveillance, so repeat hormonal testing not required

ESA Guidelines for Hyperaldosteronismm Screening

• Any patient with sustained blood pressure above 150/100 on three separate measurements taken on different days
• Hypertension resistant to 3 antihypertensives
• Hypertension controlled with four or more medications
• Hypertension and low potassium
• Hypertension and a newly diagnosed adrenal incidentaloma
• Hypertension and concomitant sleep apnea
• Hypertension and a family history of early onset hypertension or stroke before age 40
• All first-degree relatives of patients with a diagnosis of primary aldosteronism

Imaging

• Identification of intracytoplasmic lipid helps differentiate benign adenomas from other causes
• Unenhanced CT: < 10HU has 71% sensitivity (29% are lipid-poor) and 98% specificity for adrenal adenoma, if < 10HU then no further imaging required
• Contrast CT: if performed for another reason, usually nondiagnostic but may provide more information on general appearance
• Washout CT: adenomas exhibit rapid contrast washout, image at 15-minutes, > 60% washout vs noncontrast (absolute washout) or > 40% washout vs arterial phase (relative washout)
• MRI: less sensitive than CT
• Functional imaging: useful if unclear tumor origin or potential malignancy
• Interval growth: > 20% increase or 5mm concerning for malignancy

Biopsy

• Only indicated if biopsy results would change management, usually for concern of metastasis from another source
• Complications: bleeding, pneumo/hemothorax, risk of HTN crisis if pheochromocytoma

Relevant Physiology and Embryology to Keep in Mind

Adrenal layers (outer to inner)

• Zona Glomerulosa: produces mineralocorticoids, mainly aldosterone, stimulated by angiotensin II
• Zona Fasciculata: produces glucocorticoids, mainly cortisol, stimulated by ACTH
• Zona Reticularis: produces sex steroids (androgens and estrogens), stimulated by ACTH
• Medulla: produces catecholamines, mainly epinephrine, stimulated by sympathetic input

Potential Congenital Abnormalities

• Agenesis: not common, usually develop normally despite renal anomalies, adrenal gland will be discoid in shape due to lack of renal interaction
• Rests: accessory tissue, can be found along path of gonadal descent, most commonly seen as hyperplastic abnormal testis tissue in CAH

Benign Adrenal Neoplasms

Adrenal Adenomas

• Prevalence: 0.5% if in 20s, 7% if 70+yo, 6% of autopsy patients
• 85-90% incidentally diagnosed adrenal masses are adenomas, with 7% of these exhibiting hormone secretion
• 1.7% nonfunctional adenomas gained function on follow-up
• The goal of the workup is to rule out malignancy and metabolic/hormonal activity
• CT imaging: < 10HU on noncontrast CT and > 40-60% contrast washout are highly likely to be adenomas
• Need for follow-up after workup is controversial due to low rates of growth and hormonal activity

Other adrenal lesions (all are rare)

• Oncocytoma: > 30% reported as malignant, surgery recommended
• Myelolipoma: can rupture (more common if > 10cm), diagnosed based on CT appearance, observe unless symptomatic
• Ganglioneuroma: CT may show < 40HU and stippled calcifications
• Cysts: CT imaging w/ sharply marginated fluid without enhancement, cyst excision/aspiration may be required to rule out malignancy, most can be observed

Weiss Criteria, from Campbell's

Adrenocortical carcinoma TNM staging, from AJCC

5yr survival, from Campbell's

Adrenal Malignancies

Primary Adrenocortical Carcinoma

• Common symptoms: hormonal hypersecretion (40-60%), abdominal pain/fullness (30%)
• Test for steroid hormones as well as precursor molecules
• Obtain CT/MR A/P, larger tumors more likely to be malignant (10% if > 4cm, 25% if > 6cm)
• Usually > 25HU on non-contrast imaging and < 50% washout
• Chest imaging is required, bone scan and MR head only if bone/neuro symptoms
• Weiss criteria: 3+ criteria have 100% sensitivity and 96% specificity for diagnosing malignant vs benign adrenal masses
• Surgical resection recommended, with en bloc resection
• Consider removal of mass and metastases if able to remove > 90% disease burden
• Surveill with CT C/A/P q3mo for 2-3yrs, then space out to q6mo until 5yrs postop
• XRT recommended for CNS and bone mets
• Mitotane: DDT derivative, most commonly used adjuvant chemotherapy
• Overall 5yr survival 20-47%

Metastases to the Adrenal Gland

• If history of prior malignancy, > 50% newly diagnosed adrenal lesions are metastatic disease
• Adrenalectomy recommended for RCC if radiographically abnormal or tumor thrombus in the renal vein
• Metastases tend to be lipid-poor, with > 10HU on noncontrast CT and do not show contrast washout
• Benefits of surgical resection need to be considered for each specific malignancy

Kutikov, A., P. L. Crispen, and R. G. Uzzo. "Pathophysiology, evaluation, and medical management of adrenal disorders." Campbell-Walsh Urology 12 (2020).

Hypercortisolism - Cushing Syndrome

Causes

• Exogenous: most common cause due to treatment of other conditions
• ACTH dependent: 80% due to pituitary tumor (Cushing disease), ectopic ACTH production usually secondary to malignancy
• ACTH independent: due to adrenal adenomas, carcinomas, or hyperplasia

Urologic Indications for Hypercortisol Workup

• Hypogonadal hypogonadism: consider if low T/gonadotropins and ED or libido issues
• Stones: seen in up to 50% Cushing syndrome patients, increased stone risk even after treatment for Cushing

Workup

• Low dose dexamethasone suppression test: nighttime administration of dexamethasone should suppress ACTH and therefore cause decreased cortisol levels the next morning, but patients with Cushing syndrome will not have suppressed cortisol levels due to lack of negative feedback
• Identify source by checking ACTH level - low level indicates primary adrenal, high level indicates pituitary or ectopic source
• If low ACTH, check abdominal imaging, consider exogenous sources if no adrenal lesions noted
• If high ACTH and no obvious source, screening imaging is non-diagnostic - measure ACTH levels in the inferior petrosal sinus vs peripheral plasma after CRH stimulation - high ratio indicates pituitary source whereas normal ratio indicates ectopic source

Treatment

• Exogenous steroids: taper source to prevent withdrawal
• Pituitary source: transsphenoidal surgical resection, with 60-80% cure and 25% relapse
• Solitary adrenal lesion: unilateral adrenalectomy
• Bilateral adrenal lesions or resistant to pituitary treatment: bilateral adrenalectomy
• Ectopic source: resection of ectopic source or bilateral adrenalectomy if unable to identify source (up to 35% patients)
• Medical therapies: metyrapone, aminoglutethimide, ketoconazole, etomidate, mitotane
• Nelson syndrome: pituitary adenoma growth after bilateral adrenalectomy, seen in 8-29% patients

Kutikov, A., P. L. Crispen, and R. G. Uzzo. "Pathophysiology, evaluation, and medical management of adrenal disorders." Campbell-Walsh Urology 12 (2020).

Kutikov, A., P. L. Crispen, and R. G. Uzzo. "Pathophysiology, evaluation, and medical management of adrenal disorders." Campbell-Walsh Urology 12 (2020).

Hyperaldosteronism - Conn Syndrome

Causes

• Idiopathic hyperplasia: no obvious adenoma, less likely to cause hypokalemia
• Adenoma: more likely to cause hypertension and hypokalemia
• Rare causes: adrenal carcinomas, ectopic production, familial causes

Workup

• Usually screened during workup for refractory hypertension, prevalence 2-13% depending on severity of blood pressure
• Hypokalemia seen in 17-50% patients, also may report myalgias, polyuria, headaches
• Stop spironolactone and other receptor blockers 4 weeks prior to testing
• Check morning (8-10AM) aldosterone and renin concentrations, calculate ratio (aldosterone/renin)
• If positive screening test, perform confirmatory test due to testing variability
• No need for subtype differentiation if patient is not a surgical candidate
• Genetic screening: indicated if family hx aldosteronism, age of onset < 20yo, or family hx CVAs
• CT imaging: adenomas < 10 HU, 20% less than 1cm
• Adrenal vein sampling: lateralizes source of aldosterone if not obvious on imaging, expected lateralizing ratio is > 2:1-4:1, not needed if < 40 and clear unilateral adenoma, or patients with ACC

Treatment

• Adrenalectomy for lateralizing aldosterone secretion
• Ensure Mg + Phos repletion, normalize fluid status, BP control, and stress dose cortisol
• Spironolactone (25->400mg/d) and eplerenone (25->100mg/d) for patients who are not surgical candidates

Adrenal Insufficiency - Addison Disease

Causes

• Autoimmune: most common cause in developed countries, may be seen in autoimmune polyendocrine syndrome
• Tb: most common cause in developing countries
• Sheehan syndrome: peripartum pituitary failure
• Others: hemorrhage, amyloidosis, sarcoidosis, hemochromatosis

Evaluation/Workup

• Diagnosis often made clinically, but confirmed with morning cortisol and ACTH, plus aldosterone and renin
• Adrenal crisis: hypotension unresponsive to fluid resuscitation, abdominal pain, nausea, vomiting, fever
• Mineralocorticoid deficiency only seen in primary Addison disease
• Hyperpigmentation: ACTH stimulation also increases peptides that stimulate skin melanin production

Treatment

• Treat with glucocorticoids, mineralocorticoids if necessary
• Patients need stress dose steroids prior to surgery

Kutikov, A., P. L. Crispen, and R. G. Uzzo. "Pathophysiology, evaluation, and medical management of adrenal disorders." Campbell-Walsh Urology 12 (2020).

Kutikov, A., P. L. Crispen, and R. G. Uzzo. "Pathophysiology, evaluation, and medical management of adrenal disorders." Campbell-Walsh Urology 12 (2020).

Pheochromocytoma (PCC) and Paragangliomas (Extra-adrenal PCCs)

Symptoms/Presentation

• Classic triad: headache, episodic diaphoresis, tachycardia
• Underlying cause in 0.5% HTN cases
• Epinephrine-producing tumors may cause syncopal or hypotensive episodes due to B2 vasodilation
• Norepinephrine-producing tumors cause hypertension and sweating due to A1 vasoconstriction
• Malignant PCC defined by presence of clinical metastasis
• Familial cause in 1/3 cases - MEN2A, MEN2B, VHL, NF1, PGL-1, PGL-4

Workup

• CT imaging: 10-35HU without contrast, do not exhibit rapid contrast washout
• PET: ¹⁸F-FDG is gold standard for staging, some centers use ⁶⁸Ga-DOTATATE
• Metaiodobenzylguanidine (MIBG): analog of norepinephrine, used for staging, being replaced with PET
• Metanephrines are metabolites of catecholamines, produced at a steady rate, and are more accurately detected than catecholamine episodic surges
• Obtain genetic screening if family hx, < 50yo, multiple tumors, malignancy, or bilateral disease

Treatment/Follow-Up

• Laparoscopic adrenalectomy is standard of care, although open approach may be required
• a-blockade: start phenoxybenzamine 7-14 days preop, dose 10mg BID, titrate up to maintain a systolic BP of 120-130
• B-blockade: can be used to prevent tachycardia and arrhythmias, but should never be started before a-blockade (can exacerbate HTN)
• Malignant PCC: surgery is palliative, chemotherapy consists of cyclophosphamide + vincristine + dacarbazine (CVD)
• Recurrence: up to 16% at 10yrs, surveill with annual lab screening, imaging only based on lab results

References

• AUA Core Curriculum
• Lim, SK. and K. Ho Rha. "Surgery of the Adrenal Glands." Campbell-Walsh Urology 12 (2020).
• Kutikov, A., P. L. Crispen, and R. G. Uzzo. "Pathophysiology, evaluation, and medical management of adrenal disorders." Campbell-Walsh Urology 12 (2020).