Sabella Giovanna, Centonze Giovanni, Lagano Vincenzo, Scardino Andrea, Belli Filiberto, Garzone Giovanna, Pardo Carlotta, Galbiati Daniela, Pusceddu Sara, Mangogna Alessandro, Angerilli Valentina, Fassan Matteo, Vingiani Andrea, Agnelli Luca, Pruneri Giancarlo, Gobba Stefania, Uccella Silvia, La Rosa Stefano, Sessa Fausto, Capella Carlo, Milione Massimo
1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Colorectal Surgery Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Neuroendocrinology. 2025 May 5:1-16. doi: 10.1159/000545979.
Although neuroendocrine differentiation in colorectal carcinomas (CRCs) has been extensively reported, the biological behavior of adenocarcinomas expressing synaptophysin (Syn) but lacking typical neuroendocrine morphology remains unclear.
We tested 663 conventional CRCs with non-neuroendocrine morphology for Syn expression and correlated the results with clinicopathological and molecular characteristics as well as patient survival (overall survival [OS] and disease-free survival [DFS]). The survival characteristics of Syn expression group were compared to those of conventional CRCs and subsequently to those of 14 minENs.
Syn immunohistochemical expression ≥30% was confirmed in 27 (4.1%) patients and correlated with right colon site, grade 2, marked intratumoral lymphocyte infiltrate, and BRAF p.V600E mutation. At univariate analysis, variables associated with poor OS were 10-year increase in age (p = 0.001), stage III-IV (p = 0.001), Syn ≥30% (p = 0.001), infiltrative growth (p = 0.04), and residual tumor R1-2 (p = 0.03). At multivariable analysis, Syn expression in ≥30% of gland-forming tumor cells emerged as an independent negative prognostic factor for both OS and DFS. Moreover, 10-year increase in age, stage III-IV, and Syn ≥30% (p < 0.001) were associated with poor OS and marked peritumoral lymphocyte infiltrate with longer OS (p = 0.02). Comparable results were obtained according to DFS; in addition, right colon site (p = 0.04) was associated with longer DFS while KRAS mutation (p = 0.04) was associated with poor DFS at univariate analysis. MiNEN patients showed a shorter DFS than all conventional adenocarcinomas with or without Syn expression in univariate analyses (p < 0.001).
Among conventional CRCs, we provided evidence that Syn expression is associated with worse OS and DFS and contributes to predicting clinical outcome. Future studies should explore the molecular mechanisms underlying the acquisition of the neuroendocrine phenotype to identify new targeted treatment strategies.
尽管结直肠癌（CRC）中的神经内分泌分化已被广泛报道，但表达突触素（Syn）但缺乏典型神经内分泌形态的腺癌的生物学行为仍不清楚。
我们检测了663例具有非神经内分泌形态的传统CRC的Syn表达，并将结果与临床病理、分子特征以及患者生存情况（总生存期[OS]和无病生存期[DFS]）相关联。将Syn表达组的生存特征与传统CRC的生存特征进行比较，随后与14例微神经内分泌肿瘤（MiNEN）的生存特征进行比较。
27例（4.1%）患者的Syn免疫组化表达≥30%，且与右半结肠部位、2级、肿瘤内淋巴细胞显著浸润以及BRAF p.V600E突变相关。单因素分析显示，与OS较差相关的变量包括年龄增加10岁（p = 0.001）、III-IV期（p = 0.001）、Syn≥30%（p = 0.001）、浸润性生长（p = 0.04）以及残留肿瘤R1-2（p = 0.03）。多因素分析显示，≥30%的腺管形成肿瘤细胞中Syn表达是OS和DFS的独立负性预后因素。此外，年龄增加10岁、III-IV期以及Syn≥30%（p < 0.001）与OS较差相关，而肿瘤周围淋巴细胞显著浸润与OS较长相关（p = 0.02）。根据DFS获得了类似结果；此外，单因素分析显示右半结肠部位（p = 0.04）与DFS较长相关，而KRAS突变（p = 0.04）与DFS较差相关。在单因素分析中，MiNEN患者的DFS短于所有有或无Syn表达的传统腺癌（p < 0.001）。
在传统CRC中，我们提供了证据表明Syn表达与较差的OS和DFS相关，并有助于预测临床结局。未来的研究应探索获得神经内分泌表型的潜在分子机制，以确定新的靶向治疗策略。
