Ectopic
ACTH Cushing's syndrome (EAS) is often caused by
neuroendocrine tumors (NETs) of lungs, pancreas, thymus, and other less frequent locations. Localizing the source of
ACTH can be challenging. A 64-year-old man presented with rapidly progressing fatigue, muscular weakness, and
dyspnea. He was in poor condition and showed facial redness, proximal amyotrophy, and
bruises. Laboratory disclosed
hypokalemia, metabolic
alkalosis, and markedly elevated
ACTH and
cortisol levels. Pituitary was normal on magnetic resonance imaging (MRI), and bilateral inferior petrosal sinus blood sampling with
corticotropin-releasing hormone stimulation showed no significant central-to-periphery gradient of
ACTH. Head and neck, thoracic and abdominal computerized tomography (CT), MRI,
somatostatin receptor scintigraphy (SSRS), and (18)F-deoxyglucose-positron emission tomography (FDG-PET) failed to identify the primary
tumor. (18)F-dihydroxyphenylalanine (F-
DOPA)-PET/CT unveiled a 20-mm nodule in the jejunum and a metastatic lymph node. Segmental jejunum resection showed two adjacent NETs, measuring 2.0 and 0.5 cm with a peritoneal
metastasis. The largest
tumor expressed
ACTH in 30% of cells. Following surgery, after a transient
adrenal insufficiency,
ACTH and
cortisol levels returned to normal values and remain normal over a follow-up of 26 months. Small mid-gut NETs are difficult to localize on CT or MRI, and require metabolic imaging. Owing to low mitotic activity, NETs are generally poor candidates for FDG-PET, whereas SSRS shows poor sensitivity in EAS due to intrinsically low
tumor concentration of type-2
somatostatin receptors (SST2) or to receptor down regulation by excess
cortisol. However, F-
DOPA-PET, which is related to
amine precursor uptake by NETs, has been reported to have high positive predictive value for occult EAS despite low sensitivity, and constitutes a useful alternative to more conventional methods of
tumor localization.
LEARNING POINTS: Uncontrolled high
cortisol levels in EAS can be lethal if untreated.Surgical excision is the keystone of NETs treatment, thus
tumor localization is crucial.Most cases of EAS are caused by NETs, which are located mainly in the lungs. However, small gut NETs are elusive to conventional imaging and require metabolic imaging for detection.FDG-PET, based on
tumor high metabolic rate, may not detect NETs that have low mitotic activity. SSRS may also fail, due to absent or low concentration of SST2, which may be down regulated by excess
cortisol.F-
DOPA-PET, based on
amine-precursor uptake, can be a useful method to localize the occult source of
ACTH in EAS when other methods have failed.