Department of Pathology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
Public Laboratory, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
Histopathology. 2023 Oct;83(4):631-646. doi: 10.1111/his.14998. Epub 2023 Jun 25.
Gastric adenocarcinoma with enteroblastic differentiation (GAED) is a rare subset of alpha-fetoprotein (AFP)-producing carcinomas with poor prognosis. However, the molecular features associated with the malignant potential of GEAD remain partially elucidated.
In this study, the relationship between clinicopathological parameters and aggressive biological behaviour was analysed in 37 patients with GAED. The results showed that GAED tended to infiltrate the deep layer of the gastric wall and possessed more frequent vascular invasion than conventional gastric adenocarcinoma (CGA) (P < 0.001). All distant metastases were observed in the GAED group, not the CGA group (P < 0.001). High HER2 expression was found in nearly 24.32% of the informative cases, and none showed EBV-encoded RNA positivity or deficient mismatch repair. The most frequently mutated gene in GAED was p53. Programmed cell death-ligand 1 (PD-L1) immunostaining revealed 13 patients with a combined positive score (CPS) ≥ 5 (65%, 13 of 20). Thus, based on these molecular markers (immunostaining, in situ hybridisation and mutation analysis), GAED may be classified as a unique subgroup of the chromosomal instability subtype with HER2 /EBV /MSS/TP53 /PD-L1 . Next-generation sequencing analyses showed that mutations in the TOPI, ELOA and NOTCH3 genes were found only in GAED, and abnormally expressed genes in GAED were significantly enriched in hepatocellular carcinoma-, gland development-, and gastric cancer-related pathways.
The HER2 /EBV /MSS/TP53 /PD-L1 profile and hepatocellular carcinoma-related pathways may be significant in the malignant potential of GAED. In addition to anti-HER2 therapy, immune check-point inhibitors may be an effective treatment option for patients with GAED.
具有肠上皮分化的胃腺癌（GAED）是一种罕见的α-胎蛋白（AFP）产生型癌，预后不良。然而，与 GAED 恶性潜能相关的分子特征仍部分阐明。
本研究分析了 37 例 GAED 患者的临床病理参数与侵袭性生物学行为的关系。结果表明，GAED 倾向于浸润胃壁深层，且血管侵犯较常规胃腺癌（CGA）更为频繁（P<0.001）。所有远处转移均发生在 GAED 组，而 CGA 组未发生（P<0.001）。高 HER2 表达在近 24.32%的信息病例中发现，且无一例 EBV 编码 RNA 阳性或错配修复缺陷。GAED 中最常突变的基因是 p53。程序性细胞死亡配体 1（PD-L1）免疫组化显示 13 例患者的联合阳性评分（CPS）≥5（65%，20 例中有 13 例）。因此，基于这些分子标志物（免疫组化、原位杂交和突变分析），GAED 可能被归类为 HER2/EBV/MSS/TP53/PD-L1 染色体不稳定亚型的独特亚群。下一代测序分析显示，TOPI、ELOA 和 NOTCH3 基因的突变仅在 GAED 中发现，GAED 中异常表达的基因在肝癌、腺体发育和胃癌相关途径中显著富集。
HER2/EBV/MSS/TP53/PD-L1 谱和肝癌相关途径可能对 GAED 的恶性潜能具有重要意义。除抗 HER2 治疗外，免疫检查点抑制剂可能是 GAED 患者的有效治疗选择。
