Identification and Initial Validation of Neuroendocrine Differentiation as a Novel Prognostic Factor in Stage II Colorectal Cancer Patients

Abstract

Introduction: Neuroendocrine differentiation is often found in colorectal cancer, but its impact on prognosis remains controversial. This study explored the association between neuroendocrine differentiation and prognosis in stage II/III colorectal cancer patients.

Methods: Between 2012 and 2018, a total of 3,441 stage II/III colorectal cancer patients were included for analysis. To verify neuroendocrine differentiation, immunohistochemistry was performed to explore the expression of chromogranin A and synaptophysin in colorectal cancer. In addition, the difference in overall survival between groups was analyzed. A Kaplan-Meier analysis was used to determine the clinicopathological characteristics significantly correlated with survival, and a Cox proportional hazards analysis was used to identify factors independently affecting overall survival prognosis. Furthermore, the findings were validated by the Gene Expression Omnibus database.

Results: Among the 3,441 stage II/III colorectal cancer patients, in comparison to patients with neuroendocrine differentiation (+), patients with neuroendocrine differentiation (+) had a poorer prognosis (p = 0.001). Furthermore, multivariate survival analysis of stage II cases revealed that tumor differentiation (p = 0.018), nerve invasion (p < 0.001), and neuroendocrine differentiation (+) (p = 0.002) were independent prognostic factors. Moreover, the prognosis of patients with neuroendocrine differentiation (+) was similar to that of patients with high-risk factors in stage II cases (p = 0.639). High chromogranin A expression was correlated with poor prognosis in stage II colorectal cancer patients in the Gene Expression Omnibus database (p < 0.001).

Conclusion: The prognosis of colorectal cancer with neuroendocrine differentiation (+) was poor, especially in stage II colorectal cancer patients. Neuroendocrine differentiation might be another high-risk factor for the prognosis of stage II colorectal cancer patients.

Keywords: Colorectal cancer; High-risk factor; Neuroendocrine differentiation; Prognosis.