Ectopic ACTH-Dependent Cushing's Syndrome Emerging at a Late Stage of a Mixed Histology Neuroendocrine Neoplasm: A Case Report

Abstract

Introduction: Neuroendocrine neoplasms encompass well-differentiated tumors (NETs) and poorly differentiated carcinomas (neuroendocrine 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 (CS), 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 with a 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 (1,726 nmol/L) and ACTH (194 ng/L) levels. Urinary free cortisol measurement was 21-fold the upper limit of the reference range (3,614.0 nmol/24 h), and cortisol concentration did not decrease after 1mg-dexamethasone suppression test (1,812 nmol/L for an expected value <50 nmol/L), confirming the ACTH-dependent CS. Thoracoabdominal computed tomography (CT) scan demonstrated progressive neoplastic disease in the liver, kidney, lymph nodes, peritoneum, and lungs. Brain magnetic resonance imaging indicated multifocal metastatic infiltration but no evidence of pituitary adenoma. Interestingly, despite a previously negative ⁶⁸Ga-DOTATATE positron emission tomography (PET)/CT performed 1 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. After the workup, the patient was admitted to a supportive care facility. Hypercortisolism symptoms were effectively managed with an adrenal enzyme inhibitor (ketoconazole) in combination with somatostatin 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.

Keywords: 68Ga-DOTATATE positron emission tomography/computed tomography; Ectopic adrenocorticotropic hormone secretion; Mixed neuroendocrine non-neuroendocrine neoplasm; Neuroendocrine neoplasm; Peptide receptor radionuclide therapy; Somatostatin receptor.

Fig. 1.

Thoraco-abdominal CT. In the thoracic region, we did not find a pulmonary embolism. There was a clear progression of pulmonary metastases. a There was an almost complete involvement of the right lower lobe and the left upper lobe (arrow). b Minor pleural effusions appeared (arrow). In the abdominal region, a known left renal metastasis and retroperitoneal lymph nodes were progressing. c There was also progression in previously identified hepatic metastases (arrow). d Progression was observed in retroperitoneal para-aortic adenopathy and in the left renal metastasis (arrow), invading the local retroperitoneal fat.

Fig. 2.

⁶⁸Ga-DOTATATE PET/CT and clinic of the patient. a Negative ⁶⁸Ga-DOTATATE PET/CT scan in July 2022, 1 year before hospital admission, with the patient not showing any signs of Cushing syndrome. b In August 2023, upon hospital admission, there was a reappearance of low to moderate SSTR expression at the lymphatic, pulmonary, peritoneal, and osseous levels (arrow), suggesting the presence of a differentiated neuroendocrine component. At this moment, the patient exhibited all the signs of Cushing syndrome.