Neuroendocrine tumors (NETs) denote a heterogeneous group of neoplasms derived from cells of predominant neuroendocrine differentiation. Although they can arise from various sites throughout the body, duodenal NETs account for only 2-3% of all gastrointestinal NETs and approximately 1-2% of all duodenal tumors. ^{1, 2} These tumors are generally characterized by their slow growth and indolent behavior; however, some may exhibit aggressive features with metastatic potential. ³

Humoral hypercalcemia of malignancy (HHM) is a paraneoplastic syndrome most commonly associated with solid organ malignancies like squamous cell carcinomas of the lung and head & neck, along with breast, ovarian, renal, and bladder carcinomas. Also, hematological malignancies like Non-Hodgkins Lymphoma (NHL) frequently report paraneoplastic hypercalcemia. ⁴ Various mechanisms by which HHM can occur are by: •

Secretion of Parathyroid Hormone related peptide (PTHrp) by the tumor,

Parathyroid hormone-related peptide (PTHrP) mimics the physiological effects of parathyroid hormone, leads to increased bone resorption and calcium reabsorption in the kidney. ⁵ The association between NETs, particularly those of duodenal origin, and HHM is exceedingly rare, with only a handful of cases reported in the literature. ^{6, 7}

This case report describes a patient with a metastatic duodenal neuroendocrine tumor presenting with humoral hypercalcemia of malignancy, highlighting the clinical challenges in diagnosis and management of this unusual presentation. This case underscores the importance of considering NET as a potential etiology in patients with unexplained hypercalcemia. ⁸ Additionally, we discuss the unique pathophysiological mechanisms involved in NET-induced HHM and review the current therapeutic approaches for both the underlying malignancy and its metabolic complications. ^{9, 10}

A 70-year-old male presented to the emergency department with a two-day history of unresponsiveness. The patient had a significant medical history of Diabetes mellitus, Hypertension, and a well-differentiated neuroendocrine tumor (NET) of the duodenum ( Figure 1), grade 2, with a Ki67 index of 18.2% and mitotic rate of 12 mitosis per 10 high-power fields. For this condition, he had previously undergone distal gastrectomy with D1 duodenal resection, followed by medical management with Octreotide (Long-Acting Release) LAR injections and Everolimus.

Despite initial interventions, subsequent Gallium 68 DOTANOC PET/CT scan revealed disease progression, demonstrating multiple somatostatin-expressing arterially enhancing metastases (approximately 12) in bilateral lobes of the liver and a peripancreatic node (as shown in Figure 2).

Based on these findings, the patient had been initiated on Peptide Receptor Radionuclide Therapy (PRRT) and had completed four cycles prior to the current presentation.

On admission, the patient was critically ill. Physical examination revealed gasping respirations, a Glasgow Coma Scale (GCS) score of 3/15, severe hypoxia with an oxygen saturation of 74% on room air, and signs of severe dehydration.

Initial laboratory investigations as depicted in Table 1 were significant for anaemia, thrombocytopenia, severe hypercalcemia with serum calcium levels of 13.1 mg/dL (corrected calcium 14.1 mg/dL), and acute kidney injury. Corrected Calcium was calculated as per the following formula ²⁰ :

Corrected Calcium (mg/dL) = 0.8 × (Normal albumin (g/dL) - patient’s albumin(g/dL)) + serum calcium (mg/dL)

Immediate management included endotracheal intubation for airway protection and aggressive intravenous fluid resuscitation.

This case highlights the rare occurrence of humoral hypercalcemia of malignancy (HHM) in a patient with metastatic duodenal neuroendocrine tumor (NET). While hypercalcemia is a common paraneoplastic manifestation in various malignancies, affecting approximately 20-30% of cancer patients, its association with NETs is notably uncommon, with an estimated prevalence of only 1-2%. ^{4, 6} Among the spectrum of NETs, pancreatic NETs have been more frequently implicated in HHM compared to those of gastrointestinal origin, making our patient’s presentation particularly noteworthy. ⁸

The pathophysiology of HHM in our patient was attributed to elevated Parathyroid Hormone- related Protein (PTHrP) levels, which is consistent with published literature. PTHrP shares significant homology with parathyroid hormone (PTH) at the N-terminal region, allowing it to bind and activate the PTH receptor, thereby inducing hypercalcemia through increased osteoclastic bone resorption and enhanced renal tubular calcium reabsorption. ¹¹ Milanesi et al. reported six cases of PTHrP-secreting NETs causing HHM, predominantly originating from the pancreas, with only one case arising from the duodenum. ¹⁰ The authors observed PTHrP levels ranging from 21 to 169 pmol/L, which is notably lower than the 252 pmol/L documented in our patient, suggesting particularly aggressive PTHrP secretion.

The clinical presentation of our patient with severe altered consciousness and profound hypercalcemia (corrected calcium of 14.06 mg/dL) aligns with the findings of Goldner et al., who demonstrated that neurological manifestations predominate when serum calcium exceeds 14 mg/dL. ¹² Similarly, Kamp et al. in their cohort analysis of GEP-NETs (Gastroenteropancreatic - NETs), found that severe hypercalcemia (>14 mg/dL) was associated with a significantly poorer prognosis and rapid clinical deterioration, consistent with our patient’s course. ¹³

Interestingly, HHM in NETs appears to correlate with higher tumor grade and proliferative indices. Our patient’s tumor exhibited a Ki-67 index of 18.2%, classifying it as grade 2. This observation is consistent with the findings of Ilias et al., who reported a positive correlation between tumor grade and incidence of paraneoplastic syndromes, including HHM, in a cohort of 90 patients with NETs. ⁹ This relationship may be attributed to the dedifferentiation process, where higher-grade NETs lose their typical neuroendocrine characteristics and acquire the ability to produce atypical hormones, including PTHrP.

The management approach for our patient involved a multifaceted strategy targeting both the hypercalcemia and the underlying malignancy. However, despite aggressive interventions including bisphosphonate therapy, hemodialysis, and previous PRRT, the patient’s outcome remained poor. This therapeutic challenge is echoed in the literature, with Ralston et al. demonstrating that survival in patients with NET-associated HHM is significantly shorter compared to those with HHM from other malignancies. ¹⁴ The authors attributed this to the rapid progression of metastatic disease and the refractory nature of hypercalcemia in these cases.

The role of Peptide Receptor Radionuclide Therapy (PRRT) in the management of metastatic NETs with paraneoplastic manifestations warrants further discussion. Kwekkeboom et al., in their analysis of 504 patients with GEP-NETs (Gastroenteropancreatic NETs) treated with PRRT, noted resolution of paraneoplastic syndromes in 39% of cases, suggesting potential efficacy. ¹⁵ However, our patient had already received four cycles of PRRT before developing HHM, indicating possible treatment resistance or disease evolution. This observation aligns with the findings of Strosberg et al., who documented that approximately 30% of initially responsive NETs develop resistance to PRRT over time, particularly those with higher proliferative indices. ¹⁶

From a molecular perspective, the mechanisms driving PTHrP secretion in NETs remain incompletely understood. Wysolmerski et al. postulated that the transcription factor RUNX2 plays a crucial role in regulating PTHrP expression in neuroendocrine cells. ¹⁷ Additionally, genomic analyses by Javle et al. identified alterations in the Calcium-Sensing Receptor (CaSR) gene in a subset of PTHrP-secreting tumors, potentially contributing to dysregulated calcium homeostasis. These molecular insights may offer potential therapeutic targets for future management strategies.

It is noteworthy that our patient exhibited low vitamin D levels concurrent with hypercalcemia, a finding reported by Galitzer et al. in approximately 40% of patients with HHM. ¹⁸ This vitamin D deficiency may represent a compensatory mechanism to mitigate hypercalcemia or could reflect nutritional compromise in advanced malignancy. Additionally, the acute kidney injury observed likely resulted from the combined effects of hypercalcemia-induced renal vasoconstriction, volume depletion, and potential nephrotoxicity from prior treatments, as detailed by Sternlicht and Glezerman in their review of renal complications in patients with malignancy. ¹⁹

Our case adds to the limited literature on HHM in duodenal NETs and emphasizes the importance of considering this rare paraneoplastic manifestation in the differential diagnosis of hypercalcemia in patients with NETs. The exceptionally high PTHrP level (252 pmol/L), the grade 2 histology, and the refractory nature of both the hypercalcemia and the underlying malignancy to established therapies, including PRRT, represent distinctive features of our case.

Despite multimodal interventions including bisphosphonate therapy, hemodialysis, and prior PRRT, the patient’s outcome was poor, reflecting the challenges in managing this paraneoplastic manifestation. This case underscores the importance of considering PTHrP- mediated hypercalcemia in the differential diagnosis of hypercalcemia in NET patients, even when other more common etiologies such as bony metastases are typically encountered. Early recognition, prompt intervention, and continued research into molecular mechanisms underlying PTHrP secretion in NETs are essential to improve outcomes in this rare but clinically significant entity.

Moving forward, we recommend routine screening for hypercalcemia in all patients with metastatic NETs and consideration of PTHrP levels in those with unexplained hypercalcemia, even in the absence of bone metastases.

Written informed consent for publication of their clinical details and/or clinical images was obtained from the relative (son) of the patient.