Background/Aim: The hypoxia-inducible factor pathway regulates the expression of a diverse group of molecules such as CA9 and CXCR4. Our aim was to investigate the expression of these markers in a series of patients with an ileal neuroendocrine tumour (IET) at various stages of tumorigenesis. Methods: The immunohistochemical expression of CA9 and CXCR4 was examined in 51 patients with a resected IET. A ‘hypoxic score’ was calculated, integrating the expression of both CA9 and CXCR4 (hypoxic score 0: absence of expression of both molecules; hypoxic score 1: expression of CXCR4 and/or CA9). Results were compared to histoprognostic factors (including tumour size, stage and grade, WHO and TNM classifications, presence of vascular or perineural invasion, presence of a fibrotic stroma and microvascular density) and to survival. Results: All tumours were well differentiated. 69% of tumours were less than 25 mm. 46% of tumours largely infiltrated the intestinal wall (≥T3, subserosa and serosa) and 90% were classified as N1 and/or 63% as M1. 57% of tumours were of grade G1, 43% of grade G2. Grade G2 (p = 0.004) and larger tumour infiltration (≥T4; p = 0.03) correlated with lower survival. Hypoxic score 1 correlated with a greater tumour size (p = 0.034), larger tumour infiltration (T3 or T4; p = 0.001), grade G2 (p = 0.046), presence of lymph node metastasis (p = 0.0066) and with lower survival of patients (p = 0.03). Conclusion: The hypoxia-inducible factors CA9 and CXCR4 were found associated to the malignant progression of neuroendocrine tumours of the ileum. Their expression may reflect higher tumour aggressivity.

Keywords:
Neuroendocrine tumours, Hypoxia, CA9, Immunohistochemistry, Small intestine
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