Alpha-fetoprotein-producing gastric cancer (AFPGC) is a rare and aggressive subtype of gastric cancer associated with poor prognosis. This study aimed to investigate the recurrent metastatic patterns and prognostic factors in AFPGC patients undergoing radical surgical resection. Data from 241 AFPGC patients diagnosed between January 2017 and January 2020 who underwent surgical resection were analyzed across multiple centers. Recurrence patterns, metastatic sites, and survival outcomes were evaluated. Univariate and multivariate analyses were performed to identify risk factors for recurrent metastasis, overall survival (OS), and disease-free survival (DFS). There is an annual increase in the proportion of AFPGC cases, rising from 3.45% in 2017 to 7.88% in 2023. Higher serum AFP level was associated with increased likelihood of lymph node metastasis (P=0.006), deeper invasion depth (P=0.000) and greater tumor diameter (P=0.036). Independent predictors of recurrent metastasis included T4 infiltration, lymph node metastasis, tumor diameter >5 cm, poorly differentiated-undifferentiated pathology, preoperative AFP>1000 ng/mL, and postoperative increasing trend in AFP levels. The 5-year OS and DFS rates were 36.5% and 34.2%, respectively, with poorer survival linked to higher preoperative AFP levels and postoperative increasing trend in AFP level. Independent risk factors for poor OS and DFS included T4 infiltration, lymph node metastasis, poorly differentiated-undifferentiated pathology, preoperative AFP>1000 ng/mL, and postoperative increasing trend in AFP. Serum AFP level can serve as a potential predictive and prognostic biomarker. Identifying independent risk factors informs risk stratification and personalized treatment for AFPGC patients.

To characterize alpha-fetoprotein (AFP)-producing gastric cancer (AFPGC) at the single-cell level and to identify regulatory factors for AFP expression and malignancy.
ScRNA-seq was performed on two tumors collected from patients with AFPGC. InferCNV and sub-clustering were applied to identify typical AFPGC cells, followed by AddModuleScore, pathway enrichment, Pseudo-time, and Scenic analyses. Data from a gastric cancer (GC) cohort were collected for conjoint analysis. The analytical results were verified by cell experiments and immunohistochemistry.
AFPGC cells are similar to hepatocytes in transcriptome and transcriptional regulation, with kinetic malignancy-related pathways, compared to the common malignant epithelium. In addition, compared to common GC cells, malignancy-related pathways, such as epithelial-mesenchymal transition (EMT) and angiogenesis, were upregulated in AFPGC. Mechanistically, Dickkopf-1 (DKK1) was found to be associated with AFP expression and malignant phenotype upon combining our scRNA-seq data with a public database, which was further verified by a series of in vitro experiments and immunohistochemistry.
We demonstrated the single-cell characteristics of AFPGC and that DKK1 facilitates AFP expression and malignancy.

BACKGROUND: Alpha‑fetoprotein-producing gastric cancer (AFPGC) is a rare type of gastric cancer with a high rate of metastasis and poor prognosis. Despite substantial progress in the treatment of many solid tumors, there are no reports of the safety and effectiveness of immune checkpoint inhibitors in combination with antiangiogenesis agents for AFPGC patients who have proficient mismatch repair.
METHODS: We describe a 69-year-old man who was diagnosed with metastatic AFPGC. After progression to chemotherapy resistance, tislelizumab combined with apatinib was administered, although the patient\'s gastroscopic pathology showed proficient mismatch repair. After three cycles of therapy, partial remission (reduced by 56%) was obtained, and the quality of life improved significantly. Surprisingly, after more than 1 year of continuous application of the combination treatment regimen, both the primary and metastatic tumors in this patient eventually disappeared, which obtained complete remission without surgery. The patient has had a progression-free survival of more than 24 months and is still continuing to benefit.
CONCLUSIONS: This case is the first example of effective treatment of AFPGC with tislelizumab combined with apatinib. The outcomes of this case suggest a highly effective and tolerable therapeutic strategy for microsatellite-stabilized AFPGC.

A 70-year-old man was diagnosed with coronavirus disease 2019 (COVID-19). The patient had suspected upper gastrointestinal bleeding during the course of the COVID-19 infection. Urgent esophagogastroduodenoscopy (EGD) was performed. However, because of mobility restrictions imposed as a COVID-19 countermeasure, EGD was done in a small hospital room. Hemostatic treatment was successful, but no sufficient close examination could be done. The patient, who was diagnosed as having alpha-fetoprotein-producing gastric cancer, died about three months later.

High serum alpha-fetoprotein (AFP) level is a predictor of poor prognosis in patients with gastric cancer (GC). AFP-producing GC (AFP-GC) is an aggressive subtype of GC characterized by a high incidence of liver metastasis and high c-Met expression. High expression of metastasis-associated colon cancer 1 (MACC1), which is the transcription activator of c-Met, also predicts a poor prognosis of GC. c-Met is known to be involved in tumor progression into malignant invasive phenotypes. Considering that high c-Met expression is simultaneously positively correlated with high AFP and MACC1 expression levels and that high expression of AFP or MACC1 predicts poor prognosis in GC, we hypothesized that an interaction may exist between AFP and MACC1. In the present study, GC cell lines with AFP-overexpression, MACC1-downregulation and the combination of both transfections were used as experimental models. The relative mRNA and protein expression of c-Met, AFP and MACC1 were analyzed using reverse transcription quantitative PCR and western blotting, respectively. Cell viability was evaluated using Cell Counting Kit-8 assay. Cell invasion and cell migration were examined using Transwell migration assay with and without Matrigel, respectively. The results demonstrated that, compared with the control group, the mRNA and protein expression of MACC1was significantly elevated in the AFP-overexpressed group and in the group with AFP overexpressed and MACC1 downregulated. Furthermore, a significantly enhanced cell viability, migration and invasion were observed in the AFP-overexpressing group, whereas opposite effects were found in the MACC1-downregulating group. In summary, the results from this study indicated that AFP may promote GC progression by stimulating MACC1. This finding may help illustrating the aggressive behaviors of GC in patients with high AFP serum level and AFP-GC.

OBJECTIVE: Alpha-fetoprotein-producing gastric cancer (AFPGC) is associated with high invasion and poor prognosis, but has not been well documented due to its rarity. To develop the understanding of AFPGC, and further facilitate its clinical decision-making and treatment, we performed clinicopathological and molecular characterization of AFPGC and its two major subtypes, gastric adenocarcinoma with enteroblastic differentiation (GAED) and hepatoid adenocarcinoma (HAC).
METHODS: The clinicopathological and molecular characteristics of AFPGC patients (n = 54) were mainly investigated by immunohistochemistry and next-generation sequencing (NGS) approaches.
RESULTS: AFPGC exhibited a higher incidence of lymphatic and vascular invasion than conventional gastric adenocarcinoma (CGA). Despite various morphological patterns, there was mostly no evident difference in clinicopathological characteristics between the GAED and HAC subtypes. Target-enriched NGS profiling of disease mutation landscapes discovered 17 differentially mutated genes between AFPGC and CGA. The AFPGC patients carrying ZNF217 mutations had poorer overall survival than ZNF217 wildtype. Furthermore, ATR showed a significantly higher mutation rate in GAED than in HAC.
CONCLUSIONS: Overall, our study of clinicopathological characters shed light on the differences between CGA and AFPGC, as well as the relationships between the GAED and HAC subtypes of AFPGC. Furthermore, mutation landscape profiling revealed potential diagnostic and prognostic markers for AFPGC and its two subtypes.

Gastric adenocarcinoma with enteroblastic differentiation (GAED) is rare, highly malignant, and has higher vascular invasion and metastasis rates than conventional differentiated gastric cancer (CDGC). We report two cases of GAED that underwent curative resection by endoscopic submucosal dissection (ESD). Case 1 was an 82-year-old man with an elevated lesion in the gastric cardia. Biopsy revealed well-differentiated tubular adenocarcinoma. Pathological diagnosis of the ESD specimen revealed intramucosal gastric cancer without lymphovascular invasion (LVI). Although the surface layer of the lesion showed well and moderately differentiated tubular adenocarcinoma, clear cytoplasmic cancer cells positive for Sal-like protein-4 (SALL4) and Glypican-3 were found in a part of the deep layer. Therefore, GAED was diagnosed as present in a part of the whole lesion and covered with CDGC. Case 2 was an 83-year-old man with an elevated lesion in the gastric angulus. Biopsy revealed papillary and well-differentiated tubular adenocarcinomas. Pathological diagnosis of the ESD specimen revealed intramucosal gastric cancer without LVI. The entire lesion was occupied by papillary and tubular cancer cells, and had clear vesicles. Pure GAED was diagnosed, because the cells were SALL4 positive. In both cases, resection was curative despite the difference in pathological features.

UNASSIGNED: Alpha-fetoprotein-producing gastric cancer (AFPGC) and hepatoid adenocarcinoma of stomach (HAS) are rare types of gastric cancer, with specific clinical manifestations and poor prognosis. The standardized treatment process of such cancers remains elusive. We aim to investigate the efficacy of immunotherapy combined with chemotherapy on patients with AFPGC or HAS.
UNASSIGNED: AFPGC and HAS patients who underwent immunotherapy and/or chemotherapy as the first-line treatment at our institute from June 2016 to December 2018 were enrolled in this observational study. Their clinicopathological characteristics, serum AFP level and treatment methods were collected. The progression-free survival (PFS) and overall survival (OS) were analyzed and compared between patients who received immunotherapy plus chemotherapy and those received chemotherapy.
UNASSIGNED: A total of 21 patients with advanced AFPGC or HAS were included in the study and the median follow-up time was 28.0 months. Of the 21 patients, 7 patients received immunotherapy of PD-1 antibody (nivolumab) plus chemotherapy and 14 patients as control received chemotherapy with or without Herceptin/Apatinib. The median progression-free survival (mPFS) time was 5.0 months (4.3 months in the control group and 22.0 months in the immunotherapy group). The median overall survival (mOS) time of the control group was 16.0 months (14.0 months in chemotherapy alone subgroup, 20.0 months in chemotherapy plus Apatinib or Herceptin subgroup), while the mOS of patients receiving immunotherapy was not reached.
UNASSIGNED: This study suggested PD-1 checkpoint inhibitor plus chemotherapy could benefit AFPGC and HAS patients. Its mechanism of action warrants further investigation.

Alpha-fetoprotein (AFP)-producing gastric carcinomas (AFPGCs) are relatively rare tumors known to have a poor prognosis and commonly found as advanced lesions. Histologically, AFPGCs have been described as having hepatoid and fetal enteric (enteroblastic) morphology and are associated with conventional adenocarcinomas. Prior studies reported a hepatoid component present only in invasive areas and hypothesized that AFPGCs may develop hepatoid features during the process of tumor invasion. We report three cases of AFP-producing early gastric cancer which had an intramucosal hepatoid component. Immunohistochemistry showed that the hepatoid component was diffusely immunoreactive for SALL4, AFP, arginase-1, and HepPar1, and focally for CDX2 and PDX1. An intramucosal transition between the hepatoid component and conventional intramucosal adenocarcinoma was identified. Two patients also had a coexistent fetal enteric component, which was admixed with a hepatoid component. Although at an early stage one patient subsequently developed liver metastasis and a second patient was suspected of having liver metastasis, these were not biopsy-proven. The latter patient had a previous history of hepatocellular carcinoma (HCC) and SALL4 was used on the HCC to distinguish metastatic/further HCC from a gastric metastatic primary with hepatoid differentiation.

A 70-year-old man underwent endoscopy, which revealed a slightly depressed and elevated gastric cancer with suspected submucosal invasion of the mid gastric body. Biopsy specimens revealed differentiated tubular adenocarcinoma. We also detected lung and esophageal cancer and prioritized treatment of these lesions, and the patient underwent three endoscopies to monitor changes in gastric cancer. The tumor size and color remained unchanged; however, the marginal ridge was prominent, and the depressed area was deeper on subsequent evaluation. Total gastrectomy was performed 9 months after the first endoscopy. Histopathological examination of the resected specimens showed muscularis propria invasion, well-differentiated tubular adenocarcinoma involving the superficial mucosa, and tumor cells showing clear cytoplasm and a columnar or three-dimensional structure, between the deep mucosa and submucosa. The cells were immunopositive for Sal-like protein 4 and glypican 3; therefore, the patient was diagnosed with gastric adenocarcinoma with enteroblastic differentiation (GAED). This rare gastric cancer variant constituted approximately 70% of the entire lesion, and we observed significant lymphovascular invasion and lymph node metastasis. GAED is a rare histopathological subtype of gastric cancer described in recent years. Few cases of this tumor are reported to date; therefore, our study significantly contributes to the literature.