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ADRENALS: DIAGNOSIS AND EVALUATION OF ADRENAL MASS

• Includes 2011 CUA Incidental Adrenal Mass Gudielines
  • See 2011 CUA Incidental Adrenal Mass Guideline Notes

Background

• Definition of incidental adrenal mass: adrenal lesion >1cm discovered on radiologic examination done for reasons other than to investigate for primary adrenal disease
  • Exclusions to definition include:
    • Known malignancy or high suspicion of malignant processes [since adrenal mass has high likelihood of being a metastatic deposit]
    • Clinically overt disease
• Differential diagnosis of incidental adrenal mass (7)
  • Malignant
    1. Adrenal cortical carcinoma
    2. Metastasis
  • Benign
  1. Adenoma (functional vs. non-functional)
  2. Oncocytoma
  3. Cyst
  4. Myelolipoma
  5. Ganglioneuroma
  6. Abscess
• ≈20% of incidental adrenal masses are found to be potential surgical lesions
  • See Campbell's 11th edition Table 65-15 for Characteristics of Incidental Adrenal Masses as Described in a Systematic Review of Published Series of Adrenal Incidentalomas

Diagnosis and Evaluation

• 2011 CUA: ALL incidental adrenal masses (excluding myelolipomas, hemorrhages, and cysts) initially require a comprehensive workup, including thorough clinical, radiologic and hormonal evaluations to distinguish benign from malignant processes, as well as non-functioning from hyperfunctioning tumours.§
• UrologySchool.com Summary
  • History and physical exam
    • Screen for signs and symptoms related to disorders of
      • Adrenal hyperfunction
        1. Hypercortisolism: classic symptoms of hypercortisolism, such as central obesity, moon facies, buffalo hump, facial plethora, menstrual disturbances, hirsuitism, proximal muscle weakness, easy bruisability, and abdominal striae, are nonspecific. Systemic manifestations includedyslipidemia, insulin resistance, and hypertension
        2. Hyperaldosteronism: hypertension
        3. Pheochromocytoma: headache, episodic sudden perspiration, tachycardia
        4. Adrenal sex steroid hypersecretion
        • Hypertension classified as
          • Elevated blood pressure: SBP 120-129 mm Hg; DBP < 80 mm Hg
          • Stage 1 hypertension: SBP 130 - 139 mm Hg; DBP 80 - 89 mm Hg
          • Stage 2 hypertension: SBP ≥140 mm Hg; DBP ≥ 90 mm Hg
      • Adrenal malignancy
    • Most patients are asymptomatic
  • Labs:
    • 2011 CUA Incidental Adrenal Masses Guidelines (2-3):
      1. Low-dose dexamethasone suppression test or 24-hour urinary cortisol to rule out hypercortisolism
      2. 24-hour urinary metanephrines and/or catecholamines to rule out pheochromocytoma
      3. Aldosterone-renin ratio in patients with hypertension to rule out hyperaldosteronism
  • Imaging: unenhanced CT
    • If attenuation ≥ 10HU, obtain contrast enhanced CT with adrenal washout

Labs

• See 2011 CUA Incidental Adrenal Mass Gudieline Notes
• Hypercortisolism
  • Assessed by overnight low-dose (1 mg) dexamethasone suppression test (sensitivity: 85-90 specificity: 95-99)
    • Consideration can be given to using the 24-hour urine free cortisol (sensitivity: 80-98, specificity: 45-98) for screening, with the low dose 1 mg dexamethasone suppression test used to differentiate Cushing’s from subclinical Cushing’s syndrome if the cortisol level on the 24-hour test is elevated.
    • Further details on hypercortisolism testing
• Pheochromocytoma
  • Assessed by 24-hour urine metanephrines and catecholamines
    • Fractionated plasma metanephrines is a newer test that may be more sensitive, but less specific. As such, its use should be reserved for confirmatory testing as opposed to primary screening.
      • Plasma metanephrine testing may not be widely available outside select centres, therefore 24-hour urinary metanephrines is suggested for initial screening.
• Hyperaldosteronism
  • Assesed in hypertensive patients by upright plasma aldosterone concentration to plasma renin ratio (ARR).
    • Mineralocorticoid receptor blockers (e.g. spironolactone) and some diuretics, particularly potassium sparing diuretics (e.g. amiloride, triamterene) and potassium wasting diuretics (e.g. furosemide, HCTZ, indapamide), should be discontinued at least 4 weeks prior to the ARR
    • If ARR results are not diagnostic and hypertension can be controlled with relatively noninterfering antihypertensives, withdrawal of other potentially interfering medications (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, renin inhibitors, dihydropyridine calcium channel antagonists, β-blockers, central α-2 agonists and non-steroidal anti-inflammatory drugs) for at least 2 weeks prior to a repeat ARR is recommended.
    • While acute fluctuations in dietary sodium are reported to not affect the diagnostic accuracy of the ARR, patients should be informed to liberalize salt intake leading up to the test to ensure accurate results.
  • Normokalemia occurs in up to 50% of patients with hyperaldosteronism.
    • Traditionally, hyperadlosteronism has been clinically associated with hypertension and hypokalemia
• Adrenal Sex Steroid Hypersecretion
• Routine testing of incidentalomas for sex hormones is not currently recommended
  • Hypersecretion of adrenal sex steroids by adrenal masses, especially incidentalomas, is exceedingly rare and typically present with concomitant clinical symptoms (i.e., feminization or virilisation)
• Confirmatory hormonal testing for all positive screening tests is recommended to limit false positive results and unnecessary surgery

Imaging

• Modality
  • Ultrasound
    • Suboptimal imaging modality for detecting and characterizing adrenal lesions
  • CT
    • Unenhanced CT scan is the first test
      • Most easily interpreted test for intracellular lipid
        • Adenomas typically contain a greater proportion of intracellular fat in comparison to malignant incidentalomas.
      • Attenuation <10 HU of a region of interest over a mass on unenhanced CT corresponds to high intracytoplasmic lipid content and is diagnostic for an adrenal adenoma
        • This cutoff has ≈70% sensitivity and 98% specificity for the diagnosis of adrenal adenomas
      • ≈30% of adrenal adenomas exhibit an attenuation >10 HU on unenhanced CT owing to their lower lipid content
        • These “atypical adenomas” or "lipid-poor adenomas" are indistinguishable from non-adenomas on non-contrast CT density measurements alone
    • If attenuation > 10 HU on an unenhanced CT, obtain contrast enhanced CT with washout
      • Contrast enhanced CT with washout has excellent sensitivity and specificity in differentiating between adenomas and non-adenomatous incidentalomas
      • Phases of adrenal CT study (3):
        1. Non-contrast 5-mm images through the adrenal
        2. Enhanced (1-minute post-bolus imaging)
        3. 15-minute washout imaging
           • The diagnostic information from a single-phase enhanced CT scan for adrenal lesions is quite limited, as there is considerable overlap in post-contrast attenuation of adenomas and non-adenomas
           • Delayed (washout) imaging indicative of adrenal adenoma
             • Absolute percent washout > 60% ([Enhanced − delayed]/[Enhanced − unenhanced] × 100%)
             • Relative percent washout (RPW) > 40% ([Enhanced − delayed]/ [Enhanced] × 100%)
               • Lipid-poor adenomas possess identical properties to lipid-rich adenomas regarding their rapid loss (washout) of enhancement after CT contrast
               • RCC metastases and HCC mets may exhibit washout characteristics similar to those of lipid-poor adenomas
    • Myelolipoma, cysts and hemorrhages have distinct features on imaging
    • Characteristics of pheochromocytoma and malignant processes include (5):
      1. Size (>3 cm)
      2. Heterogenous texture
      3. Increased vascularity
      4. Attenuation of >10 HU on unenhanced CT
      5. Decreased contrast washout at 10 to 15 minutes
  • MRI
    • Similar to CT scan, chemical-shift MRI uses the lipid-rich property of most adenomas to differentiate benign from malignant
    • CT with washout is considered the gold standard and is better than chemical shift MRI for identifying adenomas
  • Functional imaging
    • The role of functional imaging for the diagnosis of pheochromocytoma is limited, given that most pheochromocytomas can be accurately diagnosed with cross-sectional imaging and metabolic evaluation for catecholamines and their metabolites.
  • PET
    • 2-[18F] FDG-PET scan can be useful in detecting metastasis in patients with a history of malignancy, as metabolically-active lesions typically have increased uptake of FDG versus benign lesions.

Adrenal biopsy

• Currently NOT recommended for the routine workup of adrenal incidentaloma
  • Limited role in contemporary era:
    1. Modern imaging in the context of clinical characteristics affords superb diagnostic capabilities
    2. Histologically, adenomas cannot be reliably differentiated from adrenal carcinomas
    3. Risks of biopsy
• Should be pursued if diagnosis remains equivocol and the result of biopsy will influence management.
  • Most useful in patients with primary malignancies that have potentially recurred in the adrenal gland and whose management will be affected by the biopsy results.
• ALWAYS exclude possibility of pheochromocytoma before biopsy to avoid potentially life-threatening hemorrhage and hypertensive crisis

Management

• Adrenalectomy
  • Indications (11):

1. Size ≥ 4 cm (with exception of myelolipoma)
   • Most adrenocortical carcinomas are >4cm in size
     • Masses >6 cm should be considered malignant until proved otherwise.
     • Although management of masses between 4-6 cm is controversial, in otherwise healthy individuals, masses >4 cm should be resected
       • Radiologically benign masses >4 cm may be followed in patients who are not prime candidates for surgery
   • The incidence of benign adrenal adenomas increases with age
     • Adrenal lesions in younger patients, even those < 4 cm, must be managed with greater caution than similar lesions in an older patient.
     • Lesions >4 cm in older patients with significant comorbidities may be better served with observation than resection
2. Size increases > 1 cm on follow-up imaging
   • Current recommendation is to resect masses that grow >1 cm; however, incidence of malignancy among these patients is low
3. Adrenal hyperfunction
   • Some patients with primary aldosteronism may be managed medically, especially if they are poor surgical candidates
   • Clinically silent adrenal hyperfunction is an area of debate.
     • Due to the potentially life-threatening complications, it is accepted that any lesions exhibiting silent pheochromocytoma, an adrenal incidentaloma with hormonal and radiologic signs of pheochromocytoma but without clinical symptoms, should be surgically removed after adequate adrenergic blockade
     • Surgery may be elected for younger patients with subclinical Cushing syndrome or those with new onset, medically resistant or deteriorating disease attributable to cortisol excess. The remainder should be admitted to follow-up and recommended for surgery if they develop clinical signs of Cushing’s syndrome.
4. Mass with imaging findings that are suggestive of malignancy (e.g., lipid poor, heterogeneous, irregular borders, infiltrates surrounding structures), regardless of size
5. Extremely large and/or symptomatic cyst or myelolipoma
6. Isolated adrenal metastasis (multidisciplinary decision making required)
7. During renal surgery for renal cell carcinoma if:
   1. Adrenal abnormal or not visualized because of large renal tumor size on imaging
   2. Vein thrombus to level of adrenal vein
8. Failed neurosurgical treatment of Cushing disease, necessitating bilateral adrenalectomy
9. Select patients with ectopic adrenocorticotropic hormone (ACTH) syndrome, requiring bilateral adrenalectomy
10. ACTH-independent macronodular adrenal hyperplasia (AIMAH)
11. Primary pigmented nodular adrenocortical disease (PPNAD)
• *First 4 consistent with CUA Incidental Adrenal Mass Guidelines

Follow-up protocol

• Myelolipomas, hemorrhages, cysts do not necessarily require further evaluation
• Non-functioning adenomas, typically < 4 cm, and masses not deemed resectable at initial diagnosis should undergo clinical, hormonal, and radiological surveillance.
• No consensus on the proper methodology for follow-up. Surveillance proposed in 2011 CUA Guidelines:
• Annual clinical and hormonal testing for up to 4 years
• There is no agreement on the best mechanism and frequency for hormonal follow-up. However, it should include the same screening tests used at primary evaluation
• Radiographic assessments (depends on lesion characteristics +/- size)
• Benign appearing masses
•  <1 cm, consider no further follow-up or enrolment in a clinical trial
• 1-2cm, first follow-up scan at 12 months if clinical picture warrants
• 2-4cm, first follow-up scan at 12 months
• Radiologically suspicious lesions not initially removed
• Any size, first follow-up scan should be at 3-6 months
• Further imaging follow-up should be directed by clinical judgment. Consider 1-3 assessments with the first 2 years of diagnosis.
• Tumours that remain stable on imaging and annual hormonal evaluation may be considered for discharge from follow-up after 4 years

Questions

1. What are the absolute and relative percent washout on CT suggestive of adrenal adenoma?
2. What is the initial imaging of choice for adrenal adenomas? What is the gold standard imaging for adrenal adenomas?

Answers

1. What are the absolute and relative percent washout on CT suggestive of adrenal adenoma?
2. What is the initial imaging of choice for adrenal adenomas? What is the gold standard imaging for adrenal adenomas?

References

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 65