Multiple hepatoid gastric adenocarcinoma: A case report and literature review

Background Hepatoid gastric adenocarcinoma (HGAC) is a rare gastric malignancy that exhibits the characteristics of differentiated hepatocellular carcinoma and gastric adenocarcinoma. Most cases of HGAC are also accompanied by an elevated serum alpha-fetoprotein (AFP) concentration. Here, we report a rare case of HGAC involving two primary lesions. Case presentation A 61-year-old man presented at our institution with the complaint of upper abdominal pain. An examination revealed a significantly elevated serum AFP concentration. Abdominal computed tomography revealed a gastric tumour with enlarged peripheral lymph nodes and a cavernous haemangioma in the right anterior hepatic lobe. The patient underwent distal gastrectomy, and postoperative histopathology revealed two hepatoid gastric adenocarcinomas. Immunohistochemically, the tumours were positive for AFP, hepatocyte and chromogranin A (CgA), with a Ki67 index >90%. Following a postoperative diagnosis of HGAC, the patient was treated with a chemotherapy regimen of oxaliplatin combined with capecitabine. At the 6-month follow-up, the patient’s serum AFP concentration returned to the normal level. No signs of recurrence were detected. Conclusions Compared with other gastric cancers, HGAC tends to be more malignant and invasive, with a poor prognosis. These tumours are also prone to liver metastasis,but for which without liver metastasis may have a better prognosis. We hope that our experience with this extremely rare case of HGAC involving two different primary lesions without liver metastasis, as well as our literature review and summary of the etiological mechanism, pathological features, treatment and prognosis, will help improve the diagnosis and treatment of HGAC.


Background
Hepatoid gastric adenocarcinoma (HGAC), which was first reported by Ishikura in 1985, 1 is a rare malignancy, accounting for only 1% of all gastric cancers. 2,3 A differentiated HGAC shares characteristics with both hepatocellular carcinoma (HCC) and gastric adenocarcinoma (GC), and is often accompanied by a high serum alphafetoprotein (AFP) concentration. However, AFP is not a definitive biomarker, as some patients with HGAC have normal serum AFP concentrations, while some gastric cancers that are not hepatoid adenocarcinomas can produce AFP. Accordingly, Nagai et al. suggested that HGAC should be diagnosed based on its histological characteristics, irrespective of its capacity to produce AFP. 4 The diagnosis of HGAC is complicated by its lack of association with unique clinical manifestations. The digestive symptoms of this tumour mainly include upper abdominal pain, abdominal distension and/or black stool. HGAC is mostly diagnosed at a middle or more advanced stage. These tumours are highly invasive and prone to lymph node (LN) and liver metastasis.
According to previous studies, the survival outcomes of patients with HGAC depends on the extent of resection of the primary and liver metastatic lesions. However, no targeted treatment scheme or standard chemotherapy regimen has been determined. The prognosis of HGAC also remains worse than that of general gastric cancer even after a successful operation, as demonstrated by Liu et al. who reported1-, 3-and 5-year survival rates of 30%, 13% and 9%, and 96%, 61% and 44% among patients with and without HGAC, respectively. 2 Here, we present an extremely rare case of HGAC with two different primary lesions and summarise the etiological mechanism, pathological features, treatment and prognosis of HGAC 4 through a literature review.

Case Presentation
A 61-year-old man visited a local hospital for gastroscopy, with the complaint of upper abdominal pain of 3 years' duration that had become increasingly frequent and severe. He had used omeprazole for this condition. Gastroscopy revealed two ulcers: a 4-cm-diameter lesion on the gastric antrum and a 2-cm-diameter lesion on the back wall of the gastric angle. Histological analysis of the gastroscopic biopsy specimen determined that both lesions met the criteria of poorly to moderately differentiated adenocarcinoma, upon which the patient was transferred to our hospital for further treatment. Upon admission, we determined that he had a more than 20-year history of gout but no history of liver disease and no notable personal or family medical history. His vital signs were stable, and a physical examination revealed no abnormalities other than mild tenderness on his upper abdomen. Accordingly, a primary diagnosis of gastric cancer with LN metastasis was made.
The patient underwent laparotomy, during which an adhesion of the upper abdomen and multiple liver nodules of the liver were observed. An approximate ascites volume of 100 ml was removed intraoperatively. Intraoperative ultrasonography revealed a haemangioma and hepatic cyst, but no metastatic nodules in the spleen, small intestine, mesocolon or Douglas fossa. Consequently, a distal gastrectomy with radical D2-lymphadenectomy and Billroth II anastomosis were performed. A gross macroscopic analysis of the resected specimen revealed two lesions located at the gastric angle (LA) and lesser curvature of the pyloric canal (LB), respectively. LA was identified as a local ulcer type (Borrmann II type) with an approximate size of 2 cm × 1 cm. This lesion was moderately hard, with no serosal involvement. LB was identified as an infiltrating ulcer type (Borrmann III type) with an approximate size of 5 cm × 3 cm. This lesion was hard, with 5 subserosal invasion ( Figure 2).
A postoperative histopathologic analysis led to the classification of both lesions as HGAC( Figure 3). LA was limited to the mucosa and submucosa, whereas LB was confirmed to have infiltrated the subserosa (Table 1), with invasion of the duodenum, vessels and nerves but not the greater omentum or incisal edge. Eight of 34 LNs were positive, and these were located in the pylorus (2/2) and in the group 3 (1/6), group 5 (1/1), group 6 (1/2), group 7 (1/5) and group 8 LNs (2/3). The TNM stage was T 3 N 3a M 0 . Via immunohistochemistry, the tumour was determined to be positive for Sal-like protein 4 (SALL4), chromogranin A (CgA) and CEA, but negative for synaptophysin. The Ki67 proliferation index was >90% positive ( Figure   4).  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 7 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  reported a patient with HGAC and multiple liver metastases who was treated with a 9 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 T 3 N 3a M 0 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.

Consent for publication:
Written informed consent was obtained from the patient for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Availability of data and materials
All data generated or analyzed during this case study are included in this published article.

Figure 2
The patient underwent laparotomy, during which an adhesion of the upper abdomen and mul Eight of 34 LNs were positive, and these were located in the pylorus (2/2) and in the group 3

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