Supplementary Material for: Ectopic ACTH-dependent Cushing’s syndrome Emerging at a Late Stage of a Mixed Histology Neuroendocrine Neoplasm: a case report

Introduction:
Neuroendocrine neoplasms (NENs) encompass well-differentiated tumors (NETs) and poorly differentiated carcinomas (NECs), which are distinguished by their clinical behavior and molecular characteristics. They can cause paraneoplastic syndromes, such as ectopic adrenocorticotropic hormone (ACTH) dependent Cushing’s syndrome, necessitating prompt recognition and management due to severe hypercortisolism.

Case presentation:
A 66-year-old patient with a 3-year history of metastatic mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) with a neuroendocrine carcinoma (NEC) and adenocarcinoma component originating from the vulva presented to the emergency department with dyspnea and fatigue. Upon clinical examination, we found widespread hyperpigmentation, a moon-face appearance, hirsutism, buffalo hump, and muscle atrophy.

Laboratory investigations revealed severe hypokalemia (2.3 mmol/L), elevated serum cortisol (1726 nmol/L) and ACTH (194 ng/L) levels. Urinary free cortisol (UFC) measurement was 21-fold the upper limit of the reference range (3614.0 nmol/24h), and cortisol concentration did not decreases after 1mg-dexamethasone suppression test (1812 nmol/L for an expected value < 50 nmol/L), confirming the ACTH-dependent Cushing's syndrome (CS).

Thoracoabdominal computed tomography (CT) scan demonstrated progressive neoplastic disease in the liver, kidney, lymph nodes, peritoneum and lungs. Brain magnetic resonance imaging (MRI) indicated multifocal metastatic infiltration, but no evidence of pituitary adenoma. (Figure 1.)

Interestingly, despite a previously negative 68Ga-DOTATATE Positron Emission Tomography (PET)/CT performed one year prior, there was moderate somatostatin receptor (SSTR) expression in lymphatic, pulmonary, peritoneal and bone tissues, suggesting the presence of a component with redifferentiation and re-expression of the SSTR. (Figure 2.)

After the work-up, the patient was admitted to a supportive care facility. Hypercortisolism symptoms were effectively managed with an adrenal enzyme inhibitor (ketoconazole) in combination with somatostatin (SST) analogs. Unfortunately, the patient was too frail to benefit from Peptide Receptor Radionuclide Therapy (PRRT).

Conclusion:
This redifferentiation phenomenon in neuroendocrine tumors should be further investigated, as patients might be, under certain conditions, eligible for PRRT. Therefore, we suggest that newly occurring paraneoplastic syndromes in patients with NEC should always be evaluated using 68Ga-DOTATATE PET/CT.