SAT-045 - Ectopic Cushing Syndrome with Negative DOTATATE PET: A Diagnostic Challenge.

Background:
Ectopic Cushing syndrome (ECS) is a rare cause of ACTH-dependent Cushing syndrome that often eludes timely diagnosis due to difficulty localizing the source. ^68Ga-DOTATATE PET/CT is widely used to localize neuroendocrine tumors (NETs), but a negative scan does not exclude an ectopic source. This case highlights the diagnostic and therapeutic challenges of ECS with negative functional imaging.

Case Presentation:
A 29-year-old male with class III obesity, hypertension, and prediabetes presented with clinical and biochemical hypercortisolism. Physical examination revealed classic cushingoid features, including violaceous striae >1 cm (abdomen, axillae), rounded facies, centripetal obesity, and proximal muscle weakness. Biochemical testing showed urinary free cortisol ~730 μg/24 h (~3× upper limit of normal), elevated ACTH (261 pg/mL), and lack of suppression with high-dose dexamethasone. Pituitary MRI showed a 4-mm microadenoma, but inferior petrosal sinus sampling (IPSS) confirmed an ectopic ACTH source. Chest CT identified a 1.1-cm left lower-lobe pulmonary nodule, but bronchoscopy and CT-guided biopsy were nondiagnostic.
Ketoconazole was discontinued for hepatotoxicity, and osilodrostat failed to control hypercortisolism. ^68Ga-DOTATATE PET/CT showed no abnormal uptake, even in the lung nodule. Despite negative functional imaging, the lung nodule was still considered the likely source by a multidisciplinary team. The patient underwent robotic-assisted left lower-lobe wedge resection. Pathology confirmed a 1.5-cm grade 1 typical pulmonary carcinoid tumor (NET). Postoperatively, ACTH and cortisol levels declined, with significant clinical improvement (weight loss, resolution of hypertension and prediabetes). A mild biochemical elevation persisted, consistent with partial remission.

Discussion:
This case underscores limitations of ^68Ga-DOTATATE PET/CT (sensitivity ~60–70% for ectopic ACTH-secreting tumors). Importantly, intrathoracic NETs are the most common sources of ECS, comprising ~50% of cases[1]; bronchial carcinoids alone account for ~20–30%[2]. Thus, a suspicious lung nodule may be the ectopic source even with negative functional imaging. Incidental pituitary microadenomas can confound the workup, reinforcing the critical role of IPSS. Surgery may be warranted despite negative scans when biochemical and anatomic evidence strongly suggest an ectopic source.

Conclusion:
Negative ^68Ga-DOTATATE PET/CT does not exclude ectopic ACTH-secreting tumors. Careful integration of biochemical testing, imaging, and multidisciplinary expertise is essential. Even after partial remission, ongoing surveillance and adjunct medical therapy may be needed to prevent long-term complications of hypercortisolism.

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