What are the etiologies and recommended work‑up for calcification of the adrenal gland?

Etiologies of Adrenal Gland Calcification

Adrenal calcification is most commonly idiopathic (72% of cases), but requires systematic evaluation to exclude calcified tumors (21%), prior hemorrhage (5%), and infiltrative disease (1%), with the critical distinction being that most calcified adrenal tumors are benign adenomas rather than malignancies. 1

Primary Etiologic Categories

The differential diagnosis breaks down into four main categories based on the largest contemporary series:

1. Idiopathic Calcification (72%)

• Represents the majority of cases with no identifiable underlying cause 1
• Often represents sequelae of unrecognized neonatal adrenal hemorrhage 2
• Typically presents as unilateral (94%), punctate or coarse calcification 1

2. Calcified Adrenal Tumors (21%)

Benign tumors (81% of calcified masses):

• Adenomas are the most common calcified tumor (69% of calcified tumors) 1
• Myelolipomas containing macroscopic fat 3
• Adrenal cysts show characteristic peripheral curvilinear calcification pattern 4
• Pheochromocytomas (rare, but critical to identify) 1

Malignant tumors (18% of calcified masses):

• Metastases are the most common calcified malignancy (67% of calcified malignancies) 1
• Adrenocortical carcinoma 1, 4
• Neuroblastoma (most common calcified adrenal mass in children) 4

3. Prior Adrenal Hemorrhage (5%)

• May result from trauma, coagulopathy, or neonatal stress 1, 2
• History of macrosomia, birth trauma, or sepsis in neonates 2

4. Infiltrative Disease (1%)

• Granulomatous infections (tuberculosis, histoplasmosis) 1, 4
• Rare infiltrative processes 1

Recommended Work-Up Algorithm

Step 1: Focused History and Physical Examination

Target specific hormone excess syndromes and malignancy risk 3:

Cortisol excess: Weight gain, central obesity, moon facies, buffalo hump, purple striae, easy bruising, proximal muscle weakness, hypertension, diabetes 3

Catecholamine excess: Episodic or sustained hypertension, headaches, palpitations, diaphoresis, anxiety, tremor, pallor 5

Aldosterone excess: Resistant hypertension, unexplained hypokalemia, muscle weakness 3

Androgen/estrogen excess: Virilization, hirsutism, deepening voice, precocious puberty, gynecomastia 3

Malignancy history: Any known extra-adrenal primary cancer significantly increases metastasis probability 3

Step 2: Mandatory Biochemical Screening

All patients with calcified adrenal masses ≥1 cm require comprehensive hormonal evaluation regardless of imaging appearance 3, 5:

• 1 mg overnight dexamethasone suppression test (measure 8 AM cortisol): >138 nmol/L (>5.0 μg/dL) indicates autonomous cortisol secretion 5

• Plasma free metanephrines or 24-hour urinary fractionated metanephrines to exclude pheochromocytoma (levels >2X upper limit confirm diagnosis) 3, 6

• Aldosterone-to-renin ratio if hypertension or hypokalemia present (ratio >20 ng/dL per ng/mL/hr indicates primary aldosteronism) 3, 5

• Serum androgens (DHEA-S, testosterone, 17-OH progesterone) if adrenocortical carcinoma suspected or virilization present 5

Step 3: Imaging Characterization

Non-contrast CT is the mandatory first-line imaging modality 3:

• ≤10 Hounsfield Units (HU): Definitively benign adenoma, 0% malignancy risk 3, 5
• >10 HU: Requires second-line imaging with contrast-enhanced washout CT or chemical shift MRI 3

Calcification pattern analysis 1, 7, 4:

• Peripheral curvilinear calcification strongly suggests adrenal cyst 4
• Punctate or coarse calcification is nonspecific 1
• Pattern must be combined with size, enhancement, and clinical context 7, 8

Step 4: Size-Based Risk Stratification

• <3 cm: Most are benign, but functional testing still mandatory 3
• 3-5 cm: Consider surgery if indeterminate or functional 3
• >5 cm: Surgical resection recommended due to higher malignancy risk 3

Critical Clinical Pitfalls to Avoid

Never biopsy before excluding pheochromocytoma—this can precipitate fatal hypertensive crisis 6

Never skip hormonal evaluation even if calcification appears benign radiologically, as imaging cannot reliably exclude functional tumors 3, 5

Adrenal biopsy is rarely indicated and should only be considered when metastatic disease from known extra-adrenal malignancy would change management, and only after pheochromocytoma is excluded 3

In pediatric patients, maintain extremely low threshold for surgical resection given the 30.8% malignancy rate in this population, with neuroblastoma being the most common calcified pediatric adrenal mass 9, 4

When to Obtain Multidisciplinary Review

Immediate consultation with endocrinology, surgery, and radiology is warranted when 3, 5:

• Imaging not consistent with benign lesion
• Evidence of hormone hypersecretion confirmed
• Tumor growth >5 mm/year on surveillance
• Adrenal surgery being considered

Follow-Up for Non-Functional Benign Lesions

Benign non-functional adenomas <4 cm with HU ≤10 require no further imaging or functional testing 3

Lesions ≥4 cm but radiologically benign require repeat imaging at 6-12 months, with adrenalectomy considered if growth >5 mm/year after repeat functional work-up 3