Immunohistochemical expression of chemokine receptor in neuroendocrine neoplasms (CXCR4) of the gastrointestinal tract: a retrospective study of 71 cases

Abstract

Aim: C-X-C motif chemokine receptor 4 (CXCR4) is expressed in many tumor entities, including gastrointestinal neuroendocrine neoplasms (GI-NENs). However, the role of CXCR4 expression in GI-NENs has been less studied. Our objective was to investigate the expression of CXCR4 in a series of GI-NENs with various clinical and pathological features. Methods: The immunohistochemical (IHC) expression of CXCR4 (clone UMB2) was examined in 71 GI-NENs and a semiquantitative immunoreactivity score (IRS) was calculated taking into consideration the intensity of the IHC reaction and the percentage of the tumor cells which showed positive expression. Results were compared with several clinical and pathological prognostic factors. Results: High CXCR4 expression was noted in 31 (43.7%) cases. Low IRS values were more frequent in NENs from the small intestine (66.7%) and stomach (60%). Also, all appendix tumors had IRS value of zero. High CXCR4 expression was noticed in 52.5% of liver metastases, compared to 40.4% primary tumors. A significant relationship was observed between the CXCR4 expression and the tumor grade (p=0.0216), and high IRS value was correlated with clinical stages III and IV (p=0.0142) and lympho-vascular invasion (p=0.0129). 74.1% of G1 neuroendocrine tumors (NETs) had a low IRS, G3 NETs showed minor differences between low (42.9%) and high (57.1%) expression and 66.7% of neuroendocrine carcinomas (NECs) presented high expression of CXCR4. Conclusions: The present study highlighted that high CXCR4 expression is associated with high grade and advanced stage GI-NENs, as well as with metastatic cases. In these cases, high CXCR4 expression could serve as an important target for CXCR4 antagonists.

CXCR4: From Signaling to Clinical Applications in Neuroendocrine Neoplasms

“…No clear agreement exists about the relationship between CXCR4 expression and GEP-NEN location. While Mai et al showed higher expression in those whose primary tumor is located in the appendix or colon (p = 0.024) [81], Popa et al showed no statistical differences among them, but greater expression in colonic primary tumors but less immunoreactive intensity in appendix ones [82]. Interestingly, no statistical differences were found in both studies between primary tumors and metastases in the intensity of expression.…”

Expression and clinical value of CXCR4 in high grade gastroenteropancreatic neuroendocrine neoplasms

“…CXCR4 is associated with the occurrence, progression, invasion, and metastasis of a variety of malignant tumors according to previous literatures (12)(13)(14)(15)(16). CXCR4 has also been considered a prognostic factor in NENs, its expression level correlates with the malignancy of NENs (17,18). In a retrospective study, Popa et al found that high CXCR4 expression was associated with high-grade advanced NENs and tumor metastasis (18).…”

“…CXCR4 has also been considered a prognostic factor in NENs, its expression level correlates with the malignancy of NENs (17,18). In a retrospective study, Popa et al found that high CXCR4 expression was associated with high-grade advanced NENs and tumor metastasis (18).…”

Molecular factors, diagnosis and management of gastrointestinal tract neuroendocrine tumors: An update

“…Chemokyne receptor 4 is expressed in GI-NETs. Its immunohistochemical expression is related to grade 3 and metastatic disease and represents a proper target therapy by antagonists of this receptor[ 47 ].…”