Evaluating The Role of Transmembrane 9 Superfamily 4 (TM9SF4) and CDX2 Expression in Preneoplastic Colonic Lesions and Colorectal Carcinoma: (An Immunohistochemical Study)

Background: Colorectal carcinoma (CRC) is one of the most commonly diagnosed cancers and a leading cause of cancer-related mortality worldwide. Transmembrane 9 Superfamily Member 4 (TM9SF4) and caudal-type homeobox transcription factor 2 (CDX2) have been implicated in colorectal tumorigenesis.
Aim: To evaluate the immunohistochemical expression of TM9SF4 and CDX2 in preneoplastic colonic lesions and CRC, and to assess their diagnostic and prognostic significance.
Materials and methods: This retrospective study included 23 CRC cases, 16 adenomas, 10 ulcerative colitis (UC) cases, and 6 normal controls. Formalin-fixed, paraffin-embedded tissue blocks were stained immunohistochemically with TM9SF4 and CDX2 antibodies. Expression was semi-quantitatively scored, and associations with clinicopathological features were analyzed using ROC curve analysis, Spearman correlation, and Monte Carlo tests.
Results: TM9SF4 showed high expression in 95.7% of CRC cases. It distinguished CRC from controls with an AUC of 0.993, 95.7% sensitivity, and 100% specificity. CDX2 achieved perfect discrimination (AUC: 1.0) between CRC and controls. Against UC and adenoma, both markers retained good sensitivity but showed reduced specificity. High TM9SF4 expression significantly correlated with tumor grade, invasion depth, stage, and lymphovascular invasion (P < 0.05). CDX2 loss was significantly associated with high tumor grade, lymph node and distant metastases, and lymphovascular invasion (P < 0.05). A strong inverse correlation between TM9SF4 and CDX2 was observed in CRC and UC cases.
Conclusion: TM9SF4 is a promising marker for CRC aggressiveness, while CDX2 remains a reliable marker of colonic differentiation. Their inverse expression highlights their potential complementary role in CRC evaluation.