Goblet cell carcinoid (GCC) is a distinct subtype of appendiceal neoplasm that exhibits unique clinical and pathologic features. We aimed to reveal the molecular profiles of GCC compared with other appendiceal tumors, such as adenocarcinomas and neuroendocrine tumors. A total of 495 appendiceal tumor samples (53 GCCs, 428 adenocarcinomas, and 14 neuroendocrine tumors) were tested with next-generation sequencing (NGS) on a 592-gene panel and IHC. Microsatellite instability (MSI)/mismatch repair (MMR) status was tested with a combination of NGS, IHC, and fragment analyses. Tumor mutational burden (TMB) was evaluated by NGS, and PD-L1 expression was tested by IHC (SP142). The most prevalent mutated genes within GCCs were TP53 (24.0%), ARID1A (15.4%), SMAD4 (9.4%), and KRAS (7.5%). Pathway-specific alterations were dominantly observed in cell cycle, MAPK, epigenetic, and TGFβ signaling pathways. GCCs as compared with adenocarcinomas exhibited significantly lower mutation rates in KRAS, GNAS, and APC, and significantly higher mutation rates in CDH1, CHEK2, CDC73, ERCC2, and FGFR2. GCCs as compared with neuroendocrine tumors showed significantly lower mutation rates in KRAS, APC, BRCA2, and FANCA. In GCCs, MSI high/MMR deficient, TMB high (≥17 mutations/Mb), and PD-L1 expression were seen in 0.0%, 0.0%, and 2.0% of tumors, respectively. No significant differences were observed in any immunotherapy-related markers examined when compared with adenocarcinomas and neuroendocrine tumors. In conclusion, GCCs had considerably distinct mutational profiles compared with appendiceal adenocarcinomas and neuroendocrine tumors. Understanding these molecular characteristics may be critical for the development of novel and more effective treatment strategies for GCC.

中文翻译：

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阑尾杯状细胞类癌的分子特征

杯状细胞类癌 (GCC) 是阑尾肿瘤的一种独特亚型，具有独特的临床和病理特征。我们旨在揭示 GCC 与其他阑尾肿瘤（如腺癌和神经内分泌肿瘤）相比的分子特征。总共 495 个阑尾肿瘤样本（53 个 GCC、428 个腺癌和 14 个神经内分泌肿瘤）在 592 基因面板和 IHC 上通过下一代测序 (NGS) 进行了测试。微卫星不稳定性 (MSI)/错配修复 (MMR) 状态通过 NGS、IHC 和片段分析的组合进行测试。通过 NGS 评估肿瘤突变负荷 (TMB)，并通过 IHC (SP142) 测试 PD-L1 表达。GCC 中最普遍的突变基因是 TP53 (24.0%)、ARID1A (15.4%)、SMAD4 (9.4%) 和 KRAS (7.5%)。在细胞周期中主要观察到通路特异性改变，MAPK、表观遗传和 TGFβ 信号通路。与腺癌相比，GCC 在 KRAS、GNAS 和 APC 中的突变率显着较低，而在 CDH1、CHEK2、CDC73、ERCC2 和 FGFR2 中的突变率显着较高。与神经内分泌肿瘤相比，GCC 在 KRAS、APC、BRCA2 和 FANCA 中的突变率显着降低。在 GCC 中，MSI 高/MMR 缺陷、TMB 高（≥17 个突变/Mb）和 PD-L1 表达分别出现在 0.0%、0.0% 和 2.0% 的肿瘤中。与腺癌和神经内分泌肿瘤相比，所检查的任何免疫治疗相关标志物均未观察到显着差异。总之，与阑尾腺癌和神经内分泌肿瘤相比，GCC 具有明显不同的突变谱。