Immunohistochemical characteristics and potential therapeutic regimens of hepatoid adenocarcinoma of the stomach: a study of 139 cases

Abstract

Hepatoid adenocarcinoma of stomach (HAS) is a special subtype of gastric cancer with poor prognosis. Immunohistochemical analysis could provide important clues for the treatment of HAS. A total of 159 patients were diagnosed as HAS and 139 were enrolled in this study. Statistical differences were determined using relative test methods and survival analyses were performed by the Kaplan-Meier method to find survival differences. All tumors in this study were negative for Epstein-Barr virus-encoded small RNAs (EBERs) and almost all showed no loss of mismatch repair (MMR) proteins and were positive for alpha fetoprotein (AFP or spalt like transcription factor 4 (SALL4). About half of the tumors had a positive programmed death-ligand 1 combined positive score (CPS) and 17.3% were positive for human epidermal growth factor receptor 2 (HER2). In addition, there was a relatively high proportion of cmet expression. We also found that HAS patients with recurrent disease treated by emerging therapy had a better survival than those treated with traditional chemotherapy (p = 0.002, median recurrence-to-death survival: 23 months versus 6 months); HAS patients who received anti-HER2 therapy or harbored MMR deficiency had favorable prognosis. Overall, high proportions of MMR protein proficiency, positivity for AFP or SALL4, overexpression of HER2, CPS and cmet, as well as negative EBER findings, are distinctive characteristics of HAS patients. While negative EBER and MMR proficiency indicate molecular features of HAS, positivity for AFP or SALL4 could aid in the diagnosis of HAS. In addition, HAS patients could benefit from anti-HER2 therapy, immunotherapy, and anti-angiogenesis therapy.

Keywords: hepatoid adenocarcinoma of stomach; immunohistochemistry; targeted therapy.

Figure 1

Pathological features. Representative images of typical immunohistochemical and pathological features of (A) HER2 0, (B) HER2 3+, (C) CPS below 1, (D) CPS = 60, absence of (E) MLH1 and (F) PMS2, intact expression of (G) MSH2 and (H) MSH6, (I) cmet 3+, and (J) HE‐stained section of hepatoid adenocarcinoma of stomach.

Figure 2

Flow diagram. A total of 159 patients were diagnosed as HAS in our center. Twenty patients were excluded according to the exclusion criteria, leaving 139 patients enrolled in this study.

Figure 3

Correlation heatmap of different IHC and clinical traits. Correlation heatmap showing IHC, clinical features, and survival outcomes along the horizontal axis and IHC along the vertical axis. The color depth of each lattice represents the relevance of these intersecting factors, according to the legend in the figure. When the statistical p value is below or equal to 0.1, the exact number is marked in the figure. BMI, Age, Max_diameter, AC_cycle, Ly_total, and Ly_positive were analyzed as continuous variables. Gender, Family_history, Received_NAC, TRG, Approach, Surgery_type, pT, PN, Location, Borrmann, Lauren, VE, NI, Ki‐67, SALL4, and AFP were analyzed as categorical variables. AC_cycle, number of adjuvant chemotherapy cycles; AFP, alpha fetoprotein; BMI, body mass index; Ly_positive, number of positive lymph nodes; Ly_total, total number of examined lymph nodes; NAC, neoadjuvant chemotherapy; NI, neural invasion; pN, pathological N stage; pT, pathological T stage; SALL4, spalt like transcription factor 4; TRG, tumor regression grade; VE, vascular embolism.

Figure 4

Immunohistochemical findings and correlations. The relationship between HER2 and (A) AFP, (B) SALL4, (C) different Ki‐67 levels, and (D) cmet expression status. All these factors have no statistical significance with HER2 expression. The relationship between CPS and (E) AFP, (F) SALL4, (G) HER2, (H) different Ki‐67 levels, and (I) cmet expression status. HAS patients with a negative AFP stain tend to have a higher CPS, but there is no statistically significant difference. The other IHC parameters have no statistical significance with CPS.

Figure 5

The survival analysis of HAS patients with different IHC status. HAS patients with different (A, G) AFP expression status, (B, H) SALL4 expression status, (C, I) HER2 expression status, (D, J) CPS status, (E, K) Ki‐67 expression status, and (F, L) cmet expression status have no significant difference in OS or RFS outcomes.

Figure 6

The survival analysis of recurrent HAS patients with different treatments. HAS patients with recurrent disease who received emerging therapy have a significantly better survival outcome than those received traditional chemotherapy.