What is the most likely diagnosis for a woman with a 3.2 cm adrenal incidentaloma, hypertension requiring multiple agents, type 2 diabetes, abnormal overnight 1 mg dexamethasone suppression test (cortisol level elevated), low plasma Adrenocorticotropic Hormone (ACTH), and normal plasma metanephrines?

Mild Autonomous Cortisol Secretion (MACS)

The most likely diagnosis is mild autonomous cortisol secretion (MACS), previously termed "subclinical Cushing's syndrome." This patient demonstrates the classic biochemical profile: cortisol non-suppression on dexamethasone testing (95 nmol/L, which fails to suppress below 50 nmol/L), suppressed ACTH indicating adrenal autonomy, and absence of overt Cushingoid features despite metabolic complications.

Diagnostic Reasoning

Biochemical Profile Analysis

• The overnight 1 mg dexamethasone suppression test showing cortisol of 95 nmol/L is abnormal and diagnostic of autonomous cortisol production 1, 2. Normal suppression requires cortisol <50 nmol/L (1.8 μg/dL), and values >50 nmol/L indicate loss of normal hypothalamic-pituitary-adrenal axis feedback 2.

• Low plasma ACTH with elevated post-dexamethasone cortisol confirms ACTH-independent (adrenal) autonomous cortisol secretion 3. This distinguishes adrenal pathology from pituitary Cushing's disease or ectopic ACTH syndrome, both of which would show elevated ACTH 3.

• Normal plasma metanephrines effectively exclude pheochromocytoma, which can occasionally co-secrete ACTH or present with adrenal masses 1, 4.

Clinical Context Supporting MACS

• The presence of hypertension requiring three agents, type 2 diabetes, and BMI of 27 kg/m² are classic metabolic comorbidities associated with MACS 5. Studies show that 12% of adrenal incidentalomas demonstrate autonomous cortisol production, frequently accompanied by hypertension (87.5% of cases), obesity (50%), and diabetes (25%) 5.

• The absence of Cushingoid features does not exclude autonomous cortisol secretion 5, 6. MACS is defined by biochemical evidence of cortisol excess without the classic physical stigmata of overt Cushing's syndrome 1.

• The 3.2 cm size falls within the typical range for cortisol-producing adenomas (2-5 cm) 5, and the CUA guideline notes that all patients with adrenal incidentalomas should be screened for autonomous cortisol secretion 1.

Why Other Diagnoses Are Excluded

Non-functioning Adenoma (Option A)

• A non-functioning adenoma would show normal cortisol suppression (<50 nmol/L) on dexamethasone testing 1, 2. This patient's cortisol of 95 nmol/L demonstrates clear autonomous function 2.

• ACTH would be normal, not suppressed, in a truly non-functioning adenoma 3.

Cushing's Disease (Option B)

• Cushing's disease is ACTH-dependent and would show elevated or inappropriately normal ACTH, not low ACTH 3, 6. The suppressed ACTH in this case indicates primary adrenal pathology, not pituitary disease 3.

• Cushing's disease originates from pituitary ACTH-secreting adenomas, which would cause bilateral adrenal hyperplasia rather than a unilateral 3.2 cm adrenal mass 6.

Ectopic ACTH Syndrome (Option C)

• Ectopic ACTH syndrome would present with markedly elevated ACTH levels (often >300 pg/mL), not suppressed ACTH 7. The low ACTH excludes any ACTH-dependent cause 3, 7.

• Ectopic ACTH typically causes severe, rapidly progressive hypercortisolism with profound hypokalemia and metabolic alkalosis, which is not present here 7.

Adrenal Carcinoma (Option E)

• While adrenal carcinoma can produce cortisol autonomously, the 3.2 cm size makes this less likely 1. Malignant lesions are typically >5 cm in patients without known malignancy, and all malignant lesions in one series were >5 cm 1.

• The clinical presentation lacks features suggesting malignancy such as rapid growth, local invasion, or virilization from excess androgen production 1.

Clinical Implications and Management

Recommended Next Steps

• Confirm the diagnosis with additional imaging characteristics on non-contrast CT 1. Benign adenomas typically show <10 Hounsfield units on unenhanced CT due to lipid content 1.

• Consider adrenalectomy in this younger patient with progressive metabolic comorbidities attributable to cortisol excess 1. The CUA guideline states that younger patients with MACS who have progressive metabolic comorbidities can be considered for adrenalectomy after shared decision-making 1.

• If surgery is pursued, warn the patient about risk of temporary adrenal insufficiency postoperatively 5. Studies show that 57% of patients with MACS develop temporary adrenal insufficiency after unilateral adrenalectomy due to chronic ACTH suppression 5.

Expected Surgical Outcomes

• Adrenalectomy in MACS patients typically improves hypertension, facilitates weight loss, and improves glycemic control 5. In one series, the majority of patients showed improvement in arterial hypertension and better metabolic control of diabetes after surgery 5.

Alternative Management

• Patients not managed surgically should undergo annual clinical screening for new or worsening associated comorbidities 1, as autonomous cortisol production may progress over time.