How are adrenal tumors classified based on their origin, hormonal activity, and malignant potential?

Classification of Adrenal Tumors

Adrenal tumors are classified into two primary categories based on anatomical origin: cortical tumors arising from the adrenal cortex (including adenomas and adrenocortical carcinoma) and medullary tumors arising from chromaffin cells (pheochromocytomas), with further subcategorization by hormonal activity (functioning vs. non-functioning) and malignant potential (benign vs. malignant). 1

Classification by Anatomical Origin

Cortical Tumors

• Adrenocortical adenomas are the most common benign adrenal tumors, arising from the adrenal cortex and typically characterized by lipid-rich content 2, 3
• Adrenocortical carcinoma (ACC) represents the primary malignancy of the adrenal cortex, with an estimated incidence of 0.5-2 new cases per million people per year 1
• Other benign cortical lesions include oncocytomas, myelolipomas (containing macroscopic fat), and adrenal cortical hyperplasia 2, 3

Medullary Tumors

• Pheochromocytomas are catecholamine-producing neuroendocrine tumors arising from chromaffin cells of the adrenal medulla 1
• Paragangliomas (PPGLs) arise from extra-adrenal paraganglia along the sympathetic chain, with combined PPGL incidence of 2-8 per million per year 1
• The term pheochromocytoma is specifically restricted to intra-adrenal chromaffin tumors, while paraganglioma refers to extra-adrenal locations 4

Metastatic Disease

• Metastases to the adrenal glands represent the most common malignant adrenal tumors overall, particularly in patients with known extra-adrenal malignancies 2, 3

Classification by Hormonal Activity

Functioning Tumors

• Glucocorticoid excess (Cushing syndrome) can result from cortisol-secreting adenomas or ACC, requiring extensive steroid hormone work-up assessing gluco-, mineralo-, sex-, and precursor-steroids 1
• Mineralocorticoid excess (Conn syndrome) presents with aldosterone-secreting adenomas causing hypertension and hypokalemia 2
• Catecholamine-secreting tumors (pheochromocytomas/paragangliomas) must be systematically assessed in all adrenal masses by measuring plasma-free or urinary-fractionated metanephrines to prevent life-threatening hypertensive crises 1
• Androgen/estrogen-secreting tumors may present with virilization or feminization, often suggesting malignancy when present 5
• Plasma methoxytyramine measurement provides useful information to assess likelihood of malignancy in catecholamine-producing tumors 1

Non-Functioning Tumors

• Non-functioning adrenal masses larger than 4 cm with irregular margins or internal heterogeneity should raise strong suspicion for adrenocortical carcinoma 1, 6
• These tumors are typically discovered incidentally during imaging for other indications (adrenal incidentalomas) 7

Classification by Malignant Potential

Benign Lesions

• Lipid-rich adenomas demonstrate ≤10 Hounsfield units (HU) on unenhanced CT, establishing the diagnosis definitively 1, 6
• Enhancement washout >60% at 15 minutes on contrast-enhanced CT suggests benign lesions 1, 6
• Signal intensity loss on opposed-phase MRI (chemical shift analysis) is highly sensitive and specific for benign adenomas containing intracellular lipid 1, 6
• Benign pheochromocytomas cannot be distinguished from malignant ones by imaging alone; malignancy is only determined by presence of metastases in sites where chromaffin tissue is not normally present 1, 8

Malignant Lesions

Adrenocortical Carcinoma

• ACC typically shows inhomogeneous appearance with irregular margins and irregular enhancement of solid components after intravenous contrast 1
• Hounsfield units >10 on unenhanced CT suggest malignancy and warrant further evaluation with contrast-enhanced CT and washout imaging 1, 6
• Histopathologic diagnosis requires Weiss score ≥3, including parameters such as mitosis, atypical mitoses, necrosis, venous invasion, sinusoidal invasion, capsular invasion, nuclear atypia, diffuse architecture, and clear cells 8
• The ENSAT TNM classification system is superior to older staging systems and divides ACC into four stages: Stage I (≤5 cm, no invasion), Stage II (>5 cm), Stage III (any size with lymph nodes or local invasion), and Stage IV (distant metastases) 9

Malignant Pheochromocytoma/Paraganglioma

• Malignancy in PPGL is defined solely by presence of metastases in locations where chromaffin tissue does not normally exist, as neither CT nor MRI can determine benign versus malignant status 1, 8
• Over 35% of PPGL have germline mutations, making genetic testing essential 7

Critical Diagnostic Algorithm

For all adrenal masses, follow this systematic approach:

1. Rule out pheochromocytoma first by measuring plasma-free or urinary-fractionated metanephrines in all cases, as these tumors can induce life-threatening crises requiring specific pre-intervention management 1

2. Obtain unenhanced CT to measure Hounsfield units as the single best criterion for diagnosing benign adenomas (≤10 HU) 1

3. If HU >10, proceed with contrast-enhanced CT with 15-minute delayed washout imaging; washout >60% suggests benign lesion 1, 6

4. If washout <60%, consider chemical-shift MRI for further characterization, as absence of signal loss is highly sensitive and specific for malignancy 6

5. Perform comprehensive hormonal evaluation including assessment of glucocorticoid, mineralocorticoid, sex steroids, and precursor steroids to identify functioning tumors and assess malignancy risk 1

Common Pitfalls to Avoid

• Never perform fine needle biopsy of suspected ACC due to risk of tumor spillage; biopsy is contraindicated in suspected pheochromocytoma and almost never justified in ACC 9, 8
• Do not rely on size alone for malignancy assessment, though tumors >4-5 cm warrant strong suspicion, and nearly all lesions <3 cm are benign 1, 6, 5
• Always exclude pheochromocytoma before any intervention to avoid potentially fatal hypertensive crisis 6
• Recognize that massive adrenocortical steroid excess impacts short-term survival and quality of life, requiring specific treatments to block hormonal effects 1
• All patients with suspected or proven ACC or PPGL should be discussed in multidisciplinary expert team meetings at initial diagnosis (ideally before surgery) and with progressive disease 1