The prognosis of hepatoid adenocarcinoma of the stomach: a propensity score-based analysis

Gastric carcinoma (GC) is not only the second most common cancer but also the third leading cause of death in China [1, 2], which poses a great threat to people’s health in China [3]. Although the incidence rate of GC has been declining steadily with the improvement of heath standards, nutrition levels and radical treatment of Helicobacter pylori, the long-term survival is far from satisfactory [4‐6]. Rare types of cancer without standard treatment modalities partly contribute to the adverse outcomes of GC. As a rare type of GC [7, 8], hepatoid adenocarcinoma of the stomach (HAS) is a special type of extrahepatic carcinoma characterized by the histological resemblance to hepatocellular carcinoma [9, 10].

In 1970, Bourreille first reported one case of α-fetoprotein-producing gastric carcinoma with liver metastasis [11]. Later, Ishikura et al. named it “hepatoid adenocarcinoma of the stomach” for primary GC [12, 13]. It was reported that this rare type of GC accounts for 0.38 to 1% of GC. In addition to similar clinical features, such as occurring mainly in elderly and male patients [7], HAS was found to be accompanied by a higher rate of lymph node and liver metastasis in comparison with GC [14, 15]. Additionally, more than 80% of HAS patients had elevated serum α-fetoprotein (AFP) levels [14, 16]. Considering the higher rate of metastasis, the prognosis of HAS has been widely reported to be inferior to that of non-HAS [17]. To the best of our knowledge, however, most studies have been limited to case reports or case series [18]. Therefore, a more systematic study with more cases is especially meaningful for the prognostic exploration of HAS.

In our study, to explore the prognosis of HAS and whether HAS can benefit from radical surgery, we conducted propensity score-based analyses on a larger number of patients with GC.

HAS comprises polygonal cells arranged in solid or trabecular form, similar to that in hepatocellular carcinoma [12, 22]. Many researchers supported that the common embryos of the stomach and liver originated from the foregut and may evolve through genetic progression and/or genetic differences [23, 24]. At present, there were two views on the prognosis of HAS and non-HAS. The majority of studies showed that HAS had a distinctly poorer prognosis than non-HAS [9, 10, 25]. However, a few reports suggested that HAS did not have a poorer prognosis. Although many researchers explored the clinical characteristics of HAS, there was still no unified standard for its diagnosis and treatment, and most of them were case reports [26]. In addition, owing to inadequate understanding of HAS and clinicians and pathologists did not pay much attention to it [21]. Therefore, it may be clinically difficult to draw a consistent conclusion of the prognostic impact of HAS. Certainly because of this, our study aimed to further elucidate whether HAS had a worse prognosis than non-HAS using a larger number of patients and whether HAS can benefit from radical surgery.

We used the propensity score matching method to eliminate the bias between HAS and non-HAS patients and then compared their prognoses. Our study showed that there was no significant difference in postoperative OS between HAS and non-HAS patients within 3 years after radical surgical resection, which is contrary to the majority of findings. The research from Liu et al. showed a significantly different prognosis between HAS and non-HAS [27]. The 1-, 3-, and 5-year survival rates of HAS and non-HAS (without AFP production) were 30, 13, and 9% and 95, 57, and 38%, respectively [27]. In their research, the incidence of liver metastasis was 75.6% (34/45), including 8.9% synchronous and 73.2% (30/41) metachronous liver metastasis [27]. However, in the study by Cheon SH et al., among 10,259 patients diagnosed with gastric adenocarcinoma and 58 patients had live-only metastases after gastric resection [28]. Our research had seven HAS patients with postoperative liver metastasis (7/73). Therefore, we boldly speculated that the patients of HAS may had a higher risk of liver metastases [7, 29] than non-HAS, and the occurrence of liver metastasis contributed to the poorer prognosis of HAS, which was consistent with the findings of some reports [12, 30, 31]. It was worth mentioning that the prognosis of patients with higher serum levels of AFP was poorer than that of patients with lower serum levels of AFP (< 500 ng/ml) [7]. Essentially, there remained no clear reasons for the poorer OS of HAS. Some researchers believe that HAS produced alpha-1 antitrypsin (AAT) and/or alpha-1 antichymotrypsin (ACT) and AFP, which enhanced invasiveness and affect immunosuppressive properties [12, 32, 33]. However, a few studies were consistent with ours. Wang et al., demonstrated that patients with HAS who underwent radical surgery had a 5-year survival rate of 41.1% [7]. Augustin G reported that a 72-year-old man was diagnosed with HAS underwent gastrectomy and splenectomy. He was still alive 24 months after surgery without distant metastasis [34]. Giustozzi G et al. reported that a HAS patient with radical surgery who underwent chemotherapy was still alive and disease-free (with a 52-month follow-up) [35]. Therefore, radical surgery and adjuvant chemotherapy may have a positive impact on the therapeutic effect [36, 37].

In our research, the univariate analysis suggested that both T and M stage were related to the OS of gastric adenocarcinoma in the groups of data before and after PSM, but the N stage had no significant relationship with prognosis in the data after propensity score matching. This finding may be attributed to the limited number of samples after PSM. In the multivariate analysis, before PSM, T and N stage, the level of EGFR, and neoadjuvant chemotherapy were independent risk factors affecting the OS of HAS and non-HAS patients. T stage, the level of CEA and EGFR and neoadjuvant chemotherapy were independent risk factors affecting the OS of HAS and non-HAS patients in the 1:1 propensity matching. The level of CEA was an independent risk factor that affected the OS of patients after radical surgery in 1:2 propensity matching. Although distant metastasis (M1) was a significant predictor of OS after PSM, we have less data on distant metastasis, it was not convincing.

Our study had several limitations. First, it was retrospective and enrolled patients in a single institutional cohort. Second, we did not include information about the patient’s postoperative chemotherapy in our study. However, we usually decided whether to give chemotherapy to patients according to their postoperative pathological results. Lastly, the follow-up time was not long enough to assess long-term prognosis. Despite these limitations, a relatively large number of patients and rigorous statistical methods made our results convincing.

There was no statistically significant difference in the overall survival time between patients with HAS and non-HAS after radical surgery and adjuvant chemotherapy. Under the condition that patients with HAS could tolerate the surgery, the choice of surgery indications and methods were the same as that of non-HAS, radical surgery was the best choice for HAS patients.