Vitamin D deficiency is a predictor marker of tumor aggressiveness in sporadic and MEN1-related well-differentiated, low-grade GEP-NET

Background: Vitamin D has several ‘noncalcemic’ implications, including effects on cell signaling and differentiation. Patients with gastroenteropancreatic (GEP) neuroendocrine tumors (NET) have an increased risk of vitamin D deficiency, due to the tumor itself, systemic therapies and abdominal surgery. However, data regarding vitamin D status are limited. Aim of this study was to evaluate 25-hydroxy-vitamin-D (25(OH)D) levels in GEP-NET patients and correlated them with markers of tumor aggressiveness. Methods: A retrospective cross-sectional study including 101 patients affected by well-differentiated, low-grade (G)1 and G2 GEP-NET (65 sporadic and 36 with multiple endocrine neoplasia type 1 (MEN1)) and 123 healthy controls, belonging from the same geographic area and matched for age, gender and BMI, was performed. Concentration of 25(OH)D, calcium, albumin, phosphorus and PTH were measured at baseline. Regarding MEN1 patients, only those with normocalcemic primary hyperparathyroidism were included. In GEP-NET, the association of 25(OH)D with tumor grading, stage, progression-free survival (PFS) and disease-specific survival (DSS) were analyzed. Results: No difference in 25(OH)D levels was observed between patients with sporadic and MEN1-related tumors (P=0.29). Considering those patients as one group, concentration of 25(OH)D was significantly lower compared to controls (mean levels 18.3±8.5 vs 24.2±7.7 ng/mL, P<0.001). Particularly, 58.4% of GEP-NET vs 29.2% controls had vitamin D deficiency (≤20 ng/mL), comprising 17.8% vs 1.6% with severe deficiency (<10 ng/mL;P<0.0001). Patients with G2 tumors and metastasis at diagnosis had significantly lower 25(OH)D levels than those with G1 (mean levels 15.6±7.7 vs 20.1±8.6 ng/mL, P=0.02) or localized tumor (mean levels 13.1±5.3 vs 19.8±8.7 ng/mL, P=0.001). A cut-off of 25(OH)D<15.7 ng/mL was associated with increased risk of G2 (P=0.01, sensitivity 66.7%, specificity 68%) and metastasis at diagnosis (P<0.0001, sensitivity 83.3%, specificity 69%) by ROC analysis. Patients with vitamin D deficiency had shorter PFS compared to those with insufficiency (median PFS 204 vs 377 months, P=0.02, HR=2.64, 95%CI 1.13–1.26) and sufficiency (median PFS undefined, P=0.002, HR=5.66, 95%CI 1.90–16.9). No correlation was observed between vitamin D status and other investigated parameters, including DSS. Conclusion: We confirmed that vitamin D deficiency is highly prevalent among sporadic and MEN1-related GEP-NET patients and it is associated with G2 and metastasized tumors. Thus, vitamin D deficiency might represent a marker of tumor aggressiveness that might help us to identify those patients with higher risk of disease progression.