Endocrine Abstracts

Background: Vascular adhesion protein-1 (VAP-1) is a novel driver of tissue inflammation and fibrosis and may contribute to fibrotic complications of neuroendocrine tumours (NETs). We studied the VAP-1 expression in midgut NETs, which are associated with desmoplasia, and carcinoid heart disease (CHD), a significant complication of metastatic midgut NETs.

Methods: Immunohistochemical analysis of paraffin-embedded midgut NETs and CHD valves were stained for VAP-1 and collagen I, with valves additionally stained for collagen III and CD31. VAP-1 expression was assessed semi-quantitatively. Circulating VAP-1 concentration was measured by Europium-based time resolved fluorescence in serum from NET-CHD positive patients (n=7), NET-CHD negative patients (n=18) and non-NET controls (n=74, metabolic syndrome but no evidence of liver disease).

Results: There was strong VAP-1 expression in the midgut NET stroma, in close association with collagen deposition (Spearman’s correlation co-efficient 0.310, P=0.281). Increased VAP-1 expression was detected in CHD valves (n=33) compared to control valves (n=6, aortic/mitral degenerative disease), P<0.001. VAP-1 expression was not seen in control valves or chords but was seen within neo-vessels within the CHD valve and the plaque. VAP-1 expression increased with plaque maturity: increasing from myxoid to collagen to elastin rich areas. In myxoid areas, VAP-1 expression was confined to cells whilst increasing in the interstitium with maturity. Increased collagen I and collagen III expression was present in both groups but to a greater extent in CHD valves, with collagen III staining more selectively. Soluble VAP-1 was significantly elevated in patients with midgut NETs (median 562.5, IQR 438.8 – 697.3 ng/ml) compared to controls (median 256.0, IQR 212.0 – 308.0 ng/ml) P<0.0001. Patients with NET-CHD positive had a significantly higher concentration (median 691.0, IQR 684.0 – 854.0 ng/ml) than NET-CHD negative patients (median 511.0, IQR 411.3 – 583.8 ng/ml), P<0.01.

Conclusion: This is the first description of VAP-1 expression in midgut NETS and CHD. We found high circulating VAP-1 levels in NET patients, with the highest concentration seen in NET-CHD positive patients. VAP-1 expression was associated with a dense collagen and stroma network, including neovascularisation development in CHD. These studies implicate VAP-1 in the pathophysiology of midgut NETs, with potential utility as a stratification tool and a novel therapeutic target.