Adrenal Gland Tumors: Causes, Symptoms, Diagnosis and Treatment — Overview, Diagnosis & Treatment Options | MyMedicPlus

Adrenal gland tumors encompass a spectrum of benign and malignant neoplasms arising from the two anatomically and functionally distinct compartments of the adrenal gland: the cortex (producing cortisol, aldosterone, and androgens) and the medulla (producing catecholamines — epinephrine and norepinephrine). The most common adrenal tumor is the benign non-functioning cortical adenoma, found as an incidental finding (adrenal incidentaloma) in approximately 4-7% of abdominal CT scans. Clinically significant adrenal pathology includes: cortisol-secreting adenomas and adrenocortical carcinoma (ACC) causing Cushing syndrome; aldosterone-secreting adenomas (Conn's syndrome) causing hypertension and hypokalemia; adrenocortical carcinoma (ACC) — a rare malignancy with an incidence of 1-2 per million annually; pheochromocytoma and paraganglioma — catecholamine-secreting tumors arising from chromaffin cells, hereditary in approximately 40% of cases; and metastatic deposits from breast, lung, renal, and colonic primaries, which collectively represent the most common adrenal malignancy. The European Society of Endocrinology (ESE) 2023 clinical practice guidelines provide updated recommendations for adrenal incidentaloma evaluation and management, including biochemical exclusion of subclinical hormonal excess and malignancy risk stratification based on imaging phenotype and tumor size.

Most adrenal tumors are sporadic, arising from acquired somatic mutations in adrenocortical or chromaffin cells without identifiable hereditary predisposition. Adrenocortical carcinoma (ACC): hereditary syndromes account for 5-10% of adult ACC and the majority of pediatric ACC — Li-Fraumeni syndrome (TP53 germline mutation) is the most important, present in approximately 3-4% of adult ACC and 50-80% of pediatric ACC; other associations include MEN1 (multiple endocrine neoplasia type 1), familial adenomatous polyposis (APC mutation), Beckwith-Wiedemann syndrome (IGF2 overexpression and CDKN1C loss), and Lynch syndrome (MMR mutations). Somatic ACC alterations: IGF2 overexpression, CTNNB1 (Wnt/beta-catenin pathway activation), CDKN2A deletion, and TERT promoter mutation. Pheochromocytoma/paraganglioma: hereditary predisposition is exceptional — approximately 40% have germline mutations in VHL (von Hippel-Lindau syndrome), RET (MEN2A/B), NF1 (neurofibromatosis type 1), SDH subunit genes (SDHA, SDHB, SDHC, SDHD — paraganglioma syndromes 1-4), MAX, and TMEM127. SDHB mutation confers the highest malignant potential (approximately 40% metastatic rate). Benign cortical adenomas arise most commonly from somatic PRKAR1A, KCNJ5, CACNA1D, ATP1A1, or PRKACA mutations activating cAMP or calcium signaling.

Clinical presentation depends critically on tumor type, hormonal secretory status, and size. Non-functioning cortical adenomas: asymptomatic by definition, discovered incidentally on CT; subclinical autonomous cortisol secretion (SACS, formerly subclinical Cushing) may cause mild metabolic complications without full Cushing syndrome. Cortisol-secreting adenoma or ACC: Cushing syndrome — central obesity with moon face, buffalo hump, peripheral muscle wasting; facial plethora; thin fragile skin with purple striae wider than 1 cm on abdomen, thighs, and breasts; proximal myopathy; hypertension; diabetes; osteoporosis; easy bruising; and clinical depression or cognitive impairment. Aldosterone-secreting adenoma (Conn's syndrome): resistant hypertension (often requiring three or more antihypertensive agents), spontaneous hypokalemia causing muscle weakness and cramps, polyuria and nocturia, headache. Androgen-secreting ACC: rapid virilization in women — hirsutism, clitoral enlargement, acne, voice deepening, menstrual irregularity; feminization in men from estrogen-secreting tumors. Pheochromocytoma: the classic triad of paroxysmal headache, diaphoresis (profuse sweating), and palpitations — occurring in episodes lasting minutes to hours; hypertension (sustained or paroxysmal), tachycardia, pallor or flushing; hypertensive crisis precipitated by exercise, medications, or surgery may be fatal if unrecognized. Large ACC: abdominal or flank pain, palpable mass, weight loss, fever, and signs of systemic hormone excess.

Imaging characterization: CT adrenal protocol evaluates Hounsfield units (HU) on unenhanced CT — below 10 HU confirms lipid-rich benign adenoma; absolute contrast washout above 60% or relative washout above 40% at 15-minute delayed imaging distinguishes adenoma from malignancy. MRI with chemical shift sequences (in-phase and out-of-phase T1) demonstrates signal intensity drop in lipid-rich adenomas. FDG-PET/CT identifies ACC and metastases by high glucose uptake. Mandatory hormonal evaluation for all adrenal masses: 1 mg overnight dexamethasone suppression test (cortisol below 1.8 μg/dL normal) for hypercortisolism; plasma or 24-hour urine metanephrines and normetanephrines for pheochromocytoma (must be excluded before any biopsy or surgery); aldosterone-to-renin ratio (ARR) for primary aldosteronism; serum DHEA-S and testosterone for androgen excess. ENSAT staging for ACC (I-IV): Stage I (less than 5 cm, confined), Stage II (greater than 5 cm, confined), Stage III (regional invasion/lymph nodes), Stage IV (distant metastases). Ki-67 proliferation index on histology and Weiss score (malignancy if 3 or more criteria met) further stratify ACC. Germline genetic testing (panel including VHL, RET, SDHB/C/D, SDHA, MAX, TMEM127, NF1) recommended in all patients with pheochromocytoma/paraganglioma; all patients with ACC below age 40.

Non-functioning adenoma below 4 cm with benign imaging features (lipid-rich, adequate washout): surveillance with repeat CT at 6-12 months; if stable, re-imaging at 4 years. Functioning adenomas (cortisol, aldosterone, androgen-secreting): laparoscopic adrenalectomy (minimally invasive, preferred for tumors below 6 cm) achieves hormonal cure. Conn's syndrome: laparoscopic adrenalectomy for confirmed unilateral adenoma; mineralocorticoid antagonists (spironolactone 25-100 mg/day or eplerenone) for bilateral hyperplasia or non-surgical candidates. Adrenocortical carcinoma (localized): complete en bloc open adrenalectomy (laparoscopic approach only for small tumors — rupture risk elevates peritoneal recurrence); adjuvant mitotane (o,p'-DDD) recommended for all completely resected ACC — target serum levels 14-20 mg/L; adjuvant chemotherapy (EDP: etoposide, doxorubicin, cisplatin) considered for high-risk resected ACC. Advanced/metastatic ACC: EDP plus mitotane (FIRM-ACT trial: median OS 14.8 months) is first-line; pembrolizumab and lenvatinib show activity in second-line. Pheochromocytoma: alpha-adrenergic blockade mandatory before surgery (phenoxybenzamine 10-40 mg/day or doxazosin) for at least 7-14 days to prevent hypertensive crisis during tumor manipulation; beta-blockade added only after adequate alpha-blockade; laparoscopic or robotic adrenalectomy. Metastatic pheochromocytoma/paraganglioma: 177Lu-DOTATATE PRRT for SSTR2-positive disease; 131I-MIBG scintigraphy-based therapy; sunitinib or cabozantinib; cyclophosphamide-vincristine-dacarbazine chemotherapy.

The prognosis for adrenal gland tumors varies markedly by tumor type and malignant potential. Benign non-functioning cortical adenomas carry an excellent prognosis — long-term survival is equivalent to the general population, though subclinical autonomous cortisol secretion may contribute to metabolic complications requiring ongoing management. Aldosterone-secreting adenomas (Conn's syndrome) treated with laparoscopic adrenalectomy achieve blood pressure cure in approximately 50% of patients and improvement in the remainder; hypertension may persist due to pre-existing secondary vascular damage from chronic hyperaldosteronism. Adrenocortical carcinoma (ACC) carries a poor prognosis: 5-year survival is approximately 35-45% for completely resected Stage I-II disease, declining to approximately 15% for Stage III and below 10% for Stage IV metastatic disease. Median overall survival for metastatic ACC treated with EDP plus mitotane is approximately 14.8 months. Pheochromocytoma treated with laparoscopic adrenalectomy achieves biochemical cure in over 95% of sporadic non-metastatic cases; 5-year survival exceeds 95%. Approximately 10-17% of pheochromocytomas have metastatic potential — determined by SDHB mutation status, tumor size above 5 cm, and extra-adrenal location; metastatic pheochromocytoma carries a median survival of approximately 5-9 years with modern systemic therapy. Factors affecting prognosis include surgical completeness (R0 margin), tumor grade and Ki-67 index, stage at diagnosis, functional hormone excess, and germline mutation status. Lifelong surveillance with annual biochemistry and imaging is essential for all patients with ACC and pheochromocytoma given the risk of late recurrence.

Most adrenal tumors cannot be prevented as they are sporadic. Individuals with hereditary syndromes predisposing to adrenal tumors — including MEN2 (RET mutation, pheochromocytoma), VHL syndrome, NF1, SDH gene mutations (paraganglioma syndrome), and Li-Fraumeni syndrome (ACC) — require systematic surveillance with annual plasma metanephrines and periodic adrenal imaging. Genetic testing of all first-degree relatives of known carriers enables prospective monitoring. Patients with hypertension that is difficult to control, episodic symptoms (sweating, palpitations), or hypokalemia should be screened for functioning adrenal tumors before attributing hypertension to essential causes. Biochemical screening before adrenal surgery prevents dangerous perioperative catecholamine crises in undiagnosed pheochromocytoma.

Any patient with an incidentally discovered adrenal mass on imaging should be referred to an endocrinologist or specialist for hormonal evaluation and imaging characterisation, even if asymptomatic, to exclude functional and malignant tumors. Symptoms suggesting hypercortisolism (unexplained weight gain, moon face, easy bruising, stretch marks, new-onset diabetes or hypertension) or hyperaldosteronism (resistant hypertension, hypokalemia) require endocrine evaluation. Episodic symptoms of pheochromocytoma — sudden severe headache, sweating, and hypertension, often triggered by exercise, stress, or certain foods — constitute a medical emergency. An abdominal mass discovered in a child, or features of virilization in a woman (hirsutism, voice deepening, menstrual disruption), should raise concern for ACC and prompt urgent specialist referral.