As noted above, HGAC has no unique clinical manifestations, tends to be diagnosed at a later disease stage and is associated with a high risk of LN and liver metastases. In an analysis of 85 cases of HGAC, Inagawa et al. reported only 11 cases of early gastric cancer.5 In that study, the patients were predominantly male (male:female ratio ~2:1) and middle-aged to elderly, and the primary lesions arose most frequently in the antral part of the stomach (60.2%), followed by the body of the stomach and fundus of the cardia and stomach. The patients had an average serum AFP concentration of 51130.1 ng/mL (range: 1.0–700,000 ng/mL) and an average tumour diameter of 6.5 cm.
A hepatoid adenocarcinoma may originate from the stomach, oesophagus, colon, gallbladder, uterus, bladder, pancreas, ovary or other organs. However, HGAC is the most common manifestation, accounting for up to 83.9% of hepatoid adenocarcinomas.6 Most patients with HGAC have an elevated serum AFP concentration according to Boureille et al., who first reported this parameter as a biomarker of GC in 1970.7 Ishikura and colleagues believe that this elevated serum AFP level is associated with the fact that the liver and stomach develop from the embryonic foregut. Therefore, some primary gastric cancer tissues exhibit differentiation toward the liver cell lineage and thus exhibit the intrinsic characteristics of both malignancies, including excess production of AFP.1 However, AFP production is only an important characteristic of HGAC but is not a prerequisite for diagnosis, as Ishikura et al. also found that some gastric cancer patients whose lesions shared similar histopathologic features with liver cancer did not exhibit elevated serum AFP concentrations.8 Other research findings have suggested that primitive hepatoid cells may exhibit some properties of pluripotent stem cells (e.g., germ cells) during the process of tumorigenesis. Consequently, abnormal differentiation can direct certain cancer cells toward the gastrointestinal or hepatic lineage, leading to increases in the serum AFP concentration consistent with liver cancer.9
Hepatic metastasis is a frequent complication of HGAC and is the main cause of death in such cases. The mechanism underlying the hepatic metastasis of HGAC may be related to the c-Met oncogene which encodes Met, a hepatocyte growth factor receptor.The rate of LN metastasis has been associated with the tumour invasion depth and presence of c-Met amplification, and Met protein is strongly expressed in patients with advanced metastatic disease and those with tumours that have invaded the serous layer. These observations suggest that strong Met protein expression induces gastric adenocarcinoma cells to become more similar to liver cancer cells and thus enables the survival of the former in liver tissues.
Currently, pathology is the gold standard for the diagnosis of HGAC. A microscopic examination of tumour tissue reveals the differentiation of gastric cancer cells into hepatoid cells. Histopathologically, HGAC is similar to HCC. In both tumour types, the tumour cells grow, proliferate and invade surrounding tissues, and this process is accompanied by obvious venous infiltration.10,11 A typical HGAC has unique histopathological features and both hepatoid and adenocarcinoma components. From an ultrastructural perspective, the tumour cells in both differentiated components form intestinal epithelial microvilli, and the tissues are all of gastrointestinal origin. HGAC shares some tumour markers with HCC and exhibits some unique markers. The adenocarcinoma components tend to be positive for α1-ACT and α1-AAT and positive or strongly positive for CEA. The liver cancer components tend to be positive or strongly positive for AFP but weakly positive or negative for CEA. The proteases α1-ACT and α1-AAT not only inhibit the activity of fibrin, but also inhibit the reaction between lectin and normal lymphocytes. These characteristics enhance the invasiveness of HGAC and enable its dissemination to the liver and other organs in the abdominal cavity.12 SALL4 expression has been detected in the near-parietal stomach, primordial germ cell tumours, enteroblastocytic adenocarcinoma, yolk sac tumours and HGAC.13 Because AFP expression in HGAC is sometimes negative and most tumours usually express glypican–3 (GPC3) and SALL4, GPC3 and SALL4 may be more useful than AFP as clinical biomarkers of HGAC. As SALL4 is not expressed in normal liver tissue or liver cancers, SALL4 expression may also help to distinguish HGAC from HCC.4,13–15 In our case, although the tumour shared morphological features with HCC, the expression of AFP and SALL4 enabled us to make a diagnosis of HGAC.
Currently, no targeted treatment for HGAC is available. Complete surgical resection of the primary gastric cancer lesions and liver metastatic lesions is required to ensure a long survival duration. However, the prognosis associated with HGAC remains worse than that of general gastric adenocarcinoma, even after a successful resection. However, complete surgical excision with subsequent systemic chemotherapy may provide a successful resolution in such cases. Takeyama et al. reported a patient with HGAC and multiple liver metastases who was treated with a combined regimen of paclitaxel and 5-fluorouracil. The patient achieved a reduction and ultimate disappearance of the metastatic lesion and a return of the serum AFP level to the normal level.16 In our patient, a combination of surgery and chemotherapy similarly led to a reduction in the serum AFP level and a lack of disease recurrence.
Most gastric cancers arise as single lesions. In our case, however, we present a rare case of HGAC with two major lesions and no liver metastases. In our case, the TNM stage was T3N3aM0 and the preoperative AFP concentration was 1147.00 ng/mL. Five days after distal gastrectomy with radical D2-lymphadenectomy, his AFP level had decreased to 312.20 ng/mL. After 6 months of combined oxaliplatin and capecitabine chemotherapy, the patient’s AFP level decreased to 8.5 ng/mL with no radiologic signs of recurrence.
In conclusion, HGAC is associated with a high degree of malignancy and poor prognosis, and no targeted treatment is currently available. HGAC may have a better prognosis for those without liver metastasis.We hope that our observations will improve the general understanding of HGAC and promote the diagnosis and treatment of HGAC by enabling an accumulation of cases. Ultimately, we hope that our findings will contribute to an improved prognosis associated with this disease.