Hepatoid adenocarcinoma of the stomach: a unique subgroup with distinct clinicopathological and molecular features

Abstract

Objectives: Hepatoid adenocarcinoma of the stomach (HAS) is characterized by histological resemblance to hepatocellular carcinoma and a poor prognosis. The aim of this study is to elucidate the clinicopathological and molecular characteristics of HAS.

Methods: Forty-two patients with HAS who received gastrectomy were enrolled in this study. Based on a panel of 483 cancer-related genes, targeted sequencing of 24 HAS and 22 clinical parameter-matched common gastric cancer (CGC) samples was performed. Prognostic factors for overall survival (OS) and disease-free survival (DFS) were analysed with the Kaplan-Meier method.

Results: The most frequently mutated gene in both HAS and CGC was TP53, with a mutation rate of 30%. Additionally, CEBPA, RPTOR, WISP3, MARK1, and CD3EAP were identified as genes with high-frequency mutations in HAS (10-20%). Copy number gains (CNGs) at 20q11.21-13.12 occurred frequently in HAS, nearly 50% of HAS tumours harboured at least one gene with a CNG at 20q11.21-13.12. This CNG tended to be related to more adverse biobehaviour, including poorer differentiation, greater vascular and nerve invasion, and greater liver metastasis. Pathway enrichment analysis revealed that the HIF-1 signalling pathway and signalling pathways regulating stem cell pluripotency were specifically enriched in HAS. The survival analysis showed that a preoperative serum AFP level ≥ 500 ng/ml was significantly associated with poorer OS (p = 0.007) and tended to be associated with poorer DFS (p = 0.05).

Conclusion: CNGs at 20q11.21-13.12 happened frequently in HAS and tended to be related to more adverse biobehaviour. The preoperative serum AFP level was a sensitive prognostic biomarker for DFS and OS.

Keywords: Chromosome 20; Copy number gain (CNG); Hepatoid adenocarcinoma of the stomach (HAS).

Fig. 1

HAS samples with different HAS cell component percentages and different AFP immunohistochemical reactivity scores. a 100% HAS cells; b 50% HAS cells, with a classic rich cytoplasmic glycogen content and transparent bodies; c 25% HAS cells; d 10% HAS cells; e strong tumour staining; f weak tumour staining

Fig. 2

a The median serum AFP level of patients with HAS with HAS cell percentages ≥ 50% and < 50% (763.0 and 22.0 ng/ml, respectively, p = 0.003). b The median serum AFP level of patients with HAS with IHC scores of 1–3 and 4–6 (19.2 and 2316.0 ng/ml, respectively, p < 0.001)

Fig. 3

Enriched pathways in HAS and CGC tumour tissues

Fig. 4

Kaplan–Meier survival plots. a The preoperative serum AFP level was associated with OS, p = 0.007. b The preoperative serum AFP level tended to be associated with DFS, p = 0.05