Abstract Background: A subset of colorectal cancers (CRCs) exhibits neuroendocrine differentiation (NED), characterized by the expression of neuroendocrine markers such as synaptophysin and chromogranin A. Although NED has been reported to be associated with aggressive behavior and poor prognosis in other cancer types, the clinicopathological and prognostic significance of NED in CRC remains unclear due to limited and inconsistent evidence. A better understanding of CRC with NED may provide insights into its molecular characteristics and potential therapeutic strategies. Methods: Patients with pathological stage II-IV CRC who underwent surgical resection at our institution between 2013 and 2017 were retrospectively analyzed. Immunohistochemical staining for synaptophysin was performed on formalin-fixed, paraffin-embedded tissue sections. NED was defined as positive when the H-score for synaptophysin was ≥4. Clinicopathological features—including lymphovascular and perineural invasion, desmoplastic reaction pattern, tumor budding grade, and poorly differentiated cluster (PDC) grade—were compared between NED-positive and NED-negative groups. Overall survival (OS) and relapse-free survival (RFS) were analyzed using Kaplan-Meier method. Results: Among 261 evaluable CRC cases, 21 (8.0%) were classified as NED-positive based on synaptophysin expression. The NED-positive group included 9 males and 12 females, with a median age of 68 years old (range, 17-91 years old). The TNM classification (8th edition) was as follows: pathological stage II (n=4, 4.1%), stage III (n=10, 9.3%), and stage IV (n=7, 12.5%) of the total cases in each stage. Compared with NED-negative CRCs, the NED-positive group more frequently exhibited the following features: perineural invasion (61.9% vs. 31.3%), high-grade tumor budding (G2/G3: 61.9% vs. 33.8%) and PDC (G2/G3: 47.6% vs. 21.3%). The median OS and RFS for the NED-positive group were 78 months and 28 months, respectively. The 5-year OS and RFS rates were 71.9% and 35.3% in the NED-positive group, compared with 75.1% and 67.1% in the NED-negative group, respectively. RFS was significantly shorter in CRCs with NED than in those without (log-rank test, p=0.0073). Conclusions: The presence of NED tended to be associated with perineural invasion and high-grade PDC, suggesting a trend toward more aggressive histopathological features. RFS was significantly shorter in CRCs with NED than in those without, indicating a possible association between NED and early recurrence. Citation Format: Yuki Yasuda, Keigo Murakami, Hideaki Karasawa, Wataru Kosaka, Yota Akamori, Ichiro Ise, Tomoyuki Ono, Megumi Murakami, Yoshihiro Sato, Gumpei Yoshimatsu, Hideyuki Suzuki, Takashi Kamei, Shinobu Ohnuma, Toru Furukawa, Michiaki Unno.. Clinicopathological and prognostic analyses of colorectal cancer with neuroendocrine differentiation abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5365.
Yasuda et al. (Fri,) studied this question.