Proximal-To-Distal Gradient and Its Implications in Differentiation and Prognosis in Colorectal Neuroendocrine Neoplasms: The RGETNE-HERACLES Study

Background: Colorectal neuroendocrine neoplasms (CR-NENs) are traditionally classified into midgut and hindgut derivatives, a binary classification that potentially oversimplifies the underlying developmental continuum. We investigated whether CR-NEN phenotype and prognosis follow a continuous proximal-to-distal gradient to identify the optimal stratification strategy. Methods: We analyzed 1,158 patients from the RGETNE registry. Anatomical location was modeled as a continuous variable using restricted cubic splines to dissect spatial trends in proliferation (Ki67), differentiation, and survival. Prognostic performance of the continuous spatial model was formally compared with categorical approaches (right/left/rectum and midgut/hindgut) using the Akaike Information Criterion (AIC). Results: A distinct proximal-to-distal gradient was observed. The continuous spline-based model provided the superior fit for Ki-67 (R2 = 0.494), outperforming categorical approaches. Anatomical position was an independent prognostic factor, with risk increasing distally in localized disease (HR 1.79; 95% CI 1.31–2.45 for rectum vs. cecum) and significant mortality differences in metastatic disease (p < 0.001). Adjuvant benefit was also heterogeneously distributed, being concentrated in distal segments. Despite the biological continuum, the embryological midgut–hindgut dichotomy yielded the most efficient statistical fit (lowest AIC) for predicting clinical recurrence. Conclusions: CR-NENs exhibit a topographical biological continuum. Continuous modeling is optimal for molecular research and characterizing tumor aggressiveness. However, for clinical risk stratification and trial design, the traditional discrete classifications (midgut–hindgut or anatomical segments) remain the most robust, parsimonious, and practically applicable surrogates.