Pancreatic neuroendocrine tumors (pNETs) are often non-functional, but a minority acquire hormone secretion later in their course. Ectopic ACTH-secreting pNETs are extremely rare and usually associated with aggressive disease and poor outcomes. We present a patient with a long-standing, initially non-functional Grade 2 pNET who developed ectopic ACTH secretion and severe metabolic disturbances after a decade of treatment and disease evolution. This case illustrates the dynamic nature of neuroendocrine tumors and the importance of vigilant biochemical surveillance, even in previously non-functional tumors.

We retrospectively reviewed the clinical course, biochemical profile, imaging, histopathology and treatments of a single patient followed over 11 years at tertiary centers. Tumor grade, metastatic pattern, systemic therapies, onset of hormonal activity and fatal complications were summarized.

A 40-year-old woman was diagnosed in 2014 with a well-differentiated Grade 2 pancreatic body NET (Ki-67 10%) after evaluation for epigastric pain and perforated duodenal ulcer. She received octreotide LAR and everolimus, followed by subtotal pancreatectomy, splenectomy and partial gastrectomy. Postoperatively she was maintained on octreotide LAR plus sunitinib, underwent radiofrequency ablation for hepatic metastases, and later received CAPTEM chemotherapy (capecitabine + temozolomide) on the background of octreotide LAR with temporary disease control. In 2021, sunitinib was discontinued after acute pancreatitis; a second liver biopsy still showed metastatic Grade 2 NET (Ki-67 8%). With further progression in 2025, octreotide LAR was combined with lenvatinib but was complicated by upper gastrointestinal bleeding and diabetic ketoacidosis. A third liver biopsy in August 2025 revealed transformation to Grade 3 NET, and oxaliplatin plus CAPTEM were initiated but soon held because of massive tumor-related GI bleeding. She subsequently presented with recurrent upper GI bleeding, shock, diabetic ketoacidosis and severe refractory hypokalemia. Endocrine evaluation demonstrated markedly elevated cortisol AM/PM(>60 pg/mL/>60 µg/dL), ACTH AM/PM (262 pg/mL/243 pg/mL) without pituitary lesions, consistent with ectopic ACTH syndrome from metastatic pNET. Despite continued somatostatin analogue therapy and intensive supportive care, she developed catastrophic intracerebral hemorrhage with brainstem compression and expired shortly thereafter.

This case illustrates late functional transformation of a previously non-functional metastatic pNET into an ACTH-secreting tumor after prolonged multimodal therapy. New red flags such as refractory hypokalemia, unexplained diabetic decompensation or rapid systemic decline in advanced pNET should prompt early screening for ectopic Cushing’s syndrome. Long-term follow-up of pNET should include periodic biochemical reassessment to detect emergent hormone secretion and to allow timely intervention before irreversible complications occur.