Multimodal management of hormonal and oncological progression in PTHrP-secreting pancreatic neuroendocrine tumours.

Summary: Parathyroid hormone-related peptide (PTHrP)-secreting pancreatic neuroendocrine tumours (Pan-NETs) are a rare cause of humoural hypercalcaemia of malignancy (HCM). We report two contrasting cases of metastatic well-differentiated PTHrP-secreting Pan-NETs (WHO grade 2; Ki-67: 7 and 8%, respectively), highlighting the variability in disease progression, response to multiple treatment modalities, and long-term outcomes. The first patient, a 55-year-old woman with mild hypercalcaemia who was largely asymptomatic except for a persistent dry cough at presentation, achieved stable disease control following eight years of treatment with somatostatin analogues (SSAs), peptide receptor radionuclide therapy (PRRT), and chemotherapy. During a prolonged period of uncontrolled hypercalcaemia prior to chemotherapy, she developed rapid bilateral hip osteoarthrosis and tumour calcification, a rare complication from long-standing calcium elevation. The second patient, a 34-year-old woman, had a more aggressive disease course, requiring multiple hospital admissions for refractory moderate-to-severe hypercalcaemia and variceal bleeding. Despite initial tumour stabilisation following PRRT, she developed refractory hypercalcaemia, demonstrating only partial response to zoledronate, high-dose denosumab, and maximal somatostatin analogue therapy, and ultimately succumbed to progressive disease and metabolic deterioration. These cases underscore the heterogeneity of PTHrP-secreting Pan-NETs and the challenges in optimising treatment strategies, given the lack of data on the optimal sequencing of therapies. Notably, calcium can serve as a reliable tumour marker for disease control, with persistent severe hypercalcaemia being a potential prognostic factor of poor outcome in patients with PTHrP-related hypercalcaemia. International collaboration and knowledge exchange are needed to ascertain the most effective management of this rare functional syndrome. Learning points: Consider PTHrP secretion in the context of hypercalcaemia in Pan-NETs.Calcium level can serve as a tumour marker in patients with PTHrP-related hypercalcaemia for assessing treatment response, disease progression, and tumour aggressiveness, with persistent hypercalcaemia being a prognostic factor for poor outcome.Hypercalcaemia may be resistant to standard treatments, and higher doses of denosumab may be necessary to achieve adequate control.An individualised multimodal treatment approach, including SSAs, PRRT, targeted therapy, chemotherapy, or a combination thereof, should be utilised to control PTHrP-secreting Pan-NETs.Although the optimal sequencing of these therapies remains unclear, multidisciplinary team discussions and shared decision-making are essential in managing such complex cases.