In a female patient with rapidly progressive Cushingoid features over 3–4 months and elevated adrenocorticotropic hormone and cortisol, what is the most likely type of Cushing syndrome?

Ectopic ACTH Secretion (Ectopic ACTH Syndrome)

The most likely diagnosis is ectopic ACTH secretion (Option D), given the rapid 3–4 month onset of severe Cushingoid features combined with elevated ACTH and cortisol levels. 1

Diagnostic Reasoning Based on Clinical Tempo

The rapid progression over 3–4 months is the critical distinguishing feature that points away from pituitary adenoma and toward ectopic ACTH syndrome:

• Ectopic ACTH syndrome typically presents with rapid onset and progression of symptoms, often developing over weeks to months, which matches this patient's 3–4 month timeline 2, 3
• Pituitary adenomas (Cushing's disease) usually develop insidiously over years, not months, making the rapid tempo atypical for this diagnosis 1, 4
• The severity of hypercortisolism in ectopic ACTH syndrome is frequently more pronounced than in pituitary disease, often presenting with florid clinical features 3, 4

ACTH-Dependent vs ACTH-Independent Classification

The laboratory findings confirm ACTH-dependent Cushing's syndrome:

• Both ACTH and cortisol are elevated, definitively establishing ACTH-dependent disease 1
• Any detectable ACTH level >5 ng/L in the setting of hypercortisolism indicates ACTH-dependent Cushing's syndrome with high certainty 1
• This immediately excludes adrenal adenoma (Option B), which would show suppressed/undetectable ACTH with elevated cortisol 1, 4
• This also excludes exogenous steroid use (Option C), which would similarly suppress endogenous ACTH production 1

Distinguishing Ectopic ACTH from Pituitary Disease

While pituitary adenomas account for 75–80% of ACTH-dependent cases overall, several factors favor ectopic ACTH in this specific presentation 1, 2:

• The 3–4 month rapid progression is highly atypical for pituitary disease but characteristic of ectopic ACTH syndrome 2, 3
• Ectopic ACTH syndrome represents approximately 10–20% of ACTH-dependent Cushing's syndrome but should be strongly suspected when clinical tempo is accelerated 2, 3, 4
• Up to 40% of patients presenting with ectopic Cushing's syndrome are found to have pulmonary carcinoid tumors, which are the most common source 5

Common Sources of Ectopic ACTH

The most prevalent tumors causing ectopic ACTH secretion include 5, 2, 3:

• Bronchial carcinoid tumors (most common)
• Small cell lung carcinoma (often presents with very rapid, severe hypercortisolism)
• Pancreatic neuroendocrine tumors
• Thymic carcinoids
• Medullary thyroid carcinoma
• Pheochromocytomas

Critical Clinical Pitfalls

Do not assume pituitary disease based solely on statistical prevalence when clinical features suggest otherwise:

• While pituitary adenomas are statistically more common overall, the rapid 3–4 month onset dramatically shifts the probability toward ectopic ACTH 2, 3
• Occult ectopic tumors are found in 12–38% of ectopic ACTH cases, meaning imaging may initially be negative despite the correct diagnosis 2
• The risk of life-threatening complications is particularly high in ectopic ACTH syndrome due to severe hypercortisolism, requiring urgent diagnosis and treatment 3, 4

Next Diagnostic Steps

If this patient were to undergo further evaluation 1:

• Pituitary MRI should still be performed to exclude a large pituitary adenoma (≥10 mm), though the rapid tempo makes this less likely
• If MRI shows no lesion or a lesion <6 mm, bilateral inferior petrosal sinus sampling (BIPSS) would be indicated to definitively distinguish pituitary from ectopic sources (central-to-peripheral ACTH ratio ≥2:1 baseline or ≥3:1 after stimulation confirms pituitary) 1
• Neck-to-pelvis thin-slice CT scan should be performed to search for neuroendocrine tumors, particularly bronchial or thymic carcinoids 1
• 68Ga-DOTATATE PET imaging can localize neuroendocrine tumors not visible on conventional imaging 1