Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy.
1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy.
Eur J Cancer. 2021 Mar;146:145-154. doi: 10.1016/j.ejca.2021.01.016. Epub 2021 Feb 16.
Neuroendocrine differentiation has been extensively associated with worse prognosis and to mechanisms of therapy resistance in several epithelial cancers. A high prevalence of neuroendocrine differentiation was recently described in mutated (BRAFmt) metastatic colorectal cancers (mCRCs) but no data are available about its prognostic impact in this setting.
We assessed synaptophysin immunohistochemical expression in a multi-institutional series of 159 BRAFmt mCRCs with matched clinical and pathological information. Tumours were dichotomized as synaptophysin high and low. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier and log-rank tests.
Thirty-five tumours (22.0%) showed any level of positivity for synaptophysin, and 18 (11.3%) were characterized by positivity in at least 20% of tumour cells. Four cases resulted 100% synaptophysin positive. The histotype of synaptophysin-positive tumours (i.e. ≥20%) was not otherwise specified in 11 cases (61.1%) and mucinous adenocarcinoma in 4 cases (22.2%). Four cases were DNA mismatch repair deficient (22.2%) and 7 (38.9%) were characterized by a high number of tumour-infiltrating lymphocytes. At multivariate analysis, high synaptophysin expression was a negative independent prognostic factor for both PFS (HR = 2.00, 95% confidence interval [CI] 1.21-3.33, p = 0.006) and OS (HR = 2.27, 95% CI 1.35-3.85, p = 0.001).
Among BRAFmt mCRCs, synaptophysin-positive tumours are characterized by worse PFS and OS. Further studies should investigate the molecular mechanisms involved in the acquisition of the neuroendocrine phenotype to identify novel-targeted treatment strategies.
神经内分泌分化已被广泛认为与几种上皮癌的预后更差和治疗耐药机制有关。最近在突变（BRAFmt）转移性结直肠癌（mCRC）中描述了神经内分泌分化的高患病率，但在这种情况下，尚无关于其预后影响的数据。
我们评估了 159 例 BRAFmt mCRC 的多机构系列中的突触素免疫组织化学表达，并具有匹配的临床和病理信息。肿瘤分为突触素高和低。通过 Kaplan-Meier 和对数秩检验评估总生存期（OS）和无进展生存期（PFS）。
35 例（22.0%）肿瘤对突触素呈任何程度的阳性，18 例（11.3%）肿瘤细胞中至少有 20%呈阳性。4 例结果为 100%突触素阳性。在突触素阳性肿瘤（即≥20%）的组织学类型中，11 例（61.1%）为未另作说明，4 例（22.2%）为黏液性腺癌。4 例为 DNA 错配修复缺陷（22.2%），7 例（38.9%）为肿瘤浸润淋巴细胞数量高。多变量分析显示，高突触素表达是 PFS（HR=2.00，95%置信区间[CI]1.21-3.33，p=0.006）和 OS（HR=2.27，95%CI 1.35-3.85，p=0.001）的独立预后不良因素。
在 BRAFmt mCRC 中，突触素阳性肿瘤的 PFS 和 OS 较差。进一步的研究应该调查获得神经内分泌表型的分子机制，以确定新的靶向治疗策略。
