A 23-year-old woman presented in May 2018 with acute left-sided hemiparesis following increasingly frequent episodes of morning drowsiness with associated weight loss. She had no significant past medical history or family history. Brain imaging excluded intracranial pathology. Blood tests during a spontaneous hypoglycaemic episode (1.5 mmol/l) identified significant hyperinsulinaemic hypoglycaemia [insulin 392 pmol/l (18173) and C-peptide 3913 pmol/l (3701470)]. MRI and 68Ga-DOTATATE-PET identified a somatostatin receptor avid pancreatic tail mass with liver metastases in segments VII/VIII and III, and a subsequent liver biopsy confirmed a well-differentiated NET (Ki-67 1%) with positive MNF116, CD56, synaptophysin and chromogranin expression. Hypoglycaemia was initially refractory to diazoxide and daily TDS octreotide therapy, and continuous 20% dextrose infusions were required to maintain normoglycaemia. Following discussion at a specialist neuroendocrine multidisciplinary meeting, she proceeded to have five cycles of Everolimus with neo-adjuvant intent together with dexamethasone and lanreotide, resulting in both rapid restoration of normoglycaemia and a radiological response suitable for one-stage surgical resection. She underwent distal pancreatectomy, splenectomy and anatomical resections of metastases in segments VII, VIII and III in November 2018, and subsequent histology confirmed a well-differentiated grade 2 NET (Ki-67 3%; final staging: pT2N1M1R0 with vascular invasion). Normoglycaemia was sustained after immediate post-operative cessation of medical therapy and no adjuvant therapy was required. No pathogenic germline variants in MEN1, CDKN1B and AIP were identified, and interval MRI/PET imaging has thus far shown no evidence of recurrence.
Summary: This case identifies a rare early-onset sporadic presentation of a large-volume metastatic insulin-secreting pancreatic NET. Multimodality therapy with somatostatin analogues, corticosteroids and the mTOR inhibitor Everolimus were administered with successful restoration of normoglycaemia despite initial lack of symptomatic response with diazoxide and octreotide. Everolimus was also given with neo-adjuvant intent, leading to a radiological response and subsequent curative surgical resection. Streptozocin-based chemotherapy was initially considered for this patient, however Everolimus was preferred due to the low proliferation index. This case also highlights the symptomatic burden associated with metastatic hormone-secreting NETs, and it is clear that early and ongoing multidisciplinary involvement is required in order to achieve optimal symptom control and treatment outcomes.