Hepatoid adenocarcinoma of the stomach effectively treated with capecitabine with oxaliplatin as adjuvant chemotherapy: A case report and literature review

Introduction Hepatoid adenocarcinoma of the stomach (HAS) is an alpha-fetoprotein (AFP)-producing gastric carcinoma (GC) with a hepatocellular carcinoma-like histology. HAS is a relatively rare type of GC, with liver metastases being more common than peritoneal dissemination in the recurrent form, and the poor prognosis. Presentation of case We present the case of a 70-year-old patient who underwent distal gastrectomy for GC and immunohistologically diagnosed as HAS. The patient had an intravenous tumor thrombus at the proximal margin of the resected stomach. Owing to the low possibility of radical resection and high probability of liver metastatic recurrence, capecitabine with oxaliplatin (CapeOX) was started as adjuvant chemotherapy (AC). After three courses of CapeOX, oxaliplatin was discontinued due to adverse events (peripheral neuropathy, grade3) and capecitabine alone was continued for 3 years postoperatively. Six years after surgery, no local recurrence or distant metastasis was detected on imaging studies. Discussion There is no established standard treatment for HAS. Recently, some studies have reported the efficacy of antimetabolites or platinum-based drugs as AC regimens. We thus decided to start a regimen consisting of a combination of antimetabolites and a platinum, i.e., CapeOX, which proved efficacious. Conclusion CapeOX or capecitabine may be effective as AC for treating HAS.


Introduction
Hepatoid adenocarcinoma of the stomach (HAS) is a rare type of gastric carcinoma (GC), first defined by Ishikura in 1985 [1], with symptoms similar to those of normal GC (abdominal discomfort, fullness of anorexia, epigastric pain, vomiting, and weight loss).
HAS is an adenocarcinoma with a histologic structure similar to hepatocellular carcinoma.
Compared to conventional GC, liver metastatic recurrence is more common than peritoneal dissemination in patients with HAS, at rates of 46.3-75.6 % [3][4][5].Owing to the infrequency of the disease and the difficulty in diagnosis, no standard treatment has been established, and there is no consensus on the chemotherapy regimen.
Here, we present a case of HAS with microscopical intravenous tumor thrombus for which capecitabine with oxaliplatin (CapeOX) was effective as adjuvant chemotherapy (AC).
This case report has been reported in line with the SCARE criteria [6].

Case presentation
A 70-year-old man with a history of hypertension and dyslipidemia Abbreviations: AC, adjuvant chemotherapy; AFP, alpha-fetoprotein; CapeOX, capecitabine with oxaliplatin; CT, computed tomography; EGD, esophagogastroduodenoscopy; GC, gastric carcinoma; H.E, hematoxylin and eosin; HAS, hepatoid adenocarcinoma of the stomach; Hep1, hep-par visited our hospital for an ulcer lesion extending from the gastric angle to antrum on esophagogastroduodenoscopy (EGD).Repeat EGD revealed the presence of a tumor with a central ulceration at the lesser curvature extending from the gastric angle to the antrum (Fig. 1a) diagnosed as a poorly differentiated adenocarcinoma by biopsy at our hospital.
Blood examination data showed an elevated serum AFP level of 122.9 ng/mL (reference range: 0.89-8.78ng/mL), while carbohydrate antigen 19-9 and carcinoembryonic antigen levels were within the reference levels.Computed tomography (CT) revealed wall thickening with contrast effect on the anterior wall of the gastric lesser curvature without invasion of other organs (Fig. 1b), with no distant metastases, and this was diagnosed as cT3N0M0 cStageIIB according to the Union for International Cancer Control (UICC) tumor node metastasis (TNM) classification 8th edition.
We performed laparoscopic distal gastrectomy with Roux-en-Y reconstruction and D2 lymph node dissection instead of total gastrectomy, because the distance from the esophagogastric junction to the oral margin of the tumor was approximately 5 cm.
The patient was started on CapeOX as adjuvant chemotherapy.The CapeOX regimen consisted of oxaliplatin 130 mg/m 2 on day 1 and capecitabine 2000 mg/m 2 on days 1-14 with a rest period on days 15-21.After three courses of CapeOX, oxaliplatin was terminated due to peripheral neuropathy (grade 3) graded according to the Common Terminology Criteria for Adverse Events.Since there was a venous tumor thrombus with a high risk of liver metastasis recurrence, capecitabine was planned to be continued as long as possible considering its adverse effects.Capecitabine was terminated after 3 years, because the adverse effect of hand-foot syndrome, progressed and reached grade 2, interfering with the patient's daily life.
The patient was followed up on an outpatient basis with blood tests every 3 months, CT every 6 months, and EGD every year.Serum AFP was elevated preoperatively but fell to within the reference range and remained within the reference range thereafter.Serum CEA and CA19-9 remained within the reference range from the preoperative period.EGD showed no evidence of recurrence of HAS or development of new residual GC in the residual stomach and CT did not show any evidence of peritoneal dissemination, local recurrence, or distant metastasis for 6 years after surgery.

Discussion
HAS, a representative AFP-producing GC, which presents a hepatocellular carcinoma-like histology, was first defined by Ishikura in 1985 [1]. HAS is relatively rare, accounting for 0.55 % of all GC cases [7].Serum AFP level can be used as an indicator of the effectiveness of postoperative treatment, in patients with HAS.Serum AFP is a useful tumor marker that correlates with prognosis [8].The histological features of HAS are similar to those of hepatocellular carcinoma, where the cells are enriched with eosinophilic cytoplasm and round nuclei on H.E staining and positive for AFP, SALL4, glypican-3 on immunohistochemical staining.Clinically, the most common site of metastasis is the liver, with a reported rate of 46.3-75.6 % [3][4][5].The 3-year survival rate is reported to be 7.36 % [9].Regarding intravenous thrombus, Yang et al. reported that intraportal tumor plugs were noted on CT in 7 (31.8%) of 22 patients with HAS, of whom 5 of 7 had intravenous tumor thrombus and liver metastases, indicating that intravenous tumor thrombus is associated with a high rate of liver metastases [10].
In our patient, the distance from the oral margin of the tumor to the resected gastric margin was 2 cm and, pathologically, the mucosa was normal, but, tumor thrombus was found at the proximal margin of the resected stomach; hence, there was a high possibility that R0 resection had not been performed, so we considered performing total residual gastrectomy with curative intent.However, the probability of liver metastasis was considered high because of the serum AFP level of ≧40 as reported by Qu et al. [8], and the high rate of liver metastatic recurrence of HAS associated with intravenous tumor thrombus as reported by Yang et al. [10], we decided to start chemotherapy rather than performing total resection of the residual stomach.Based on previous literature [9,[11][12][13][14][15][16][17] and the results of J-CLASSIC-PII trial [18], we decided to introduce a regimen consisting of a combination of antimetabolites and platinum agent, and selected CapeOX.After three courses of CapeOX, capecitabine was administered for 3 years, depending on the adverse effects, because four of the eight references used capecitabine and continued capecitabine monotherapy [9,11,14,15].After completing the course of capecitabine, the patient was followed on an outpatient basis.The patient survived for 6 years postoperatively without local recurrence or distant metastasis.

Conclusion
The patient had an intravenous tumor thrombus and a high risk of recurrence of liver metastasis.However, the patient did not show any signs of recurrence.Our case report suggests that the CapeOX or capecitabine regimen may be an effective option for AC for HAS.EPI: Epirubicin Hydrochloride CDDP: cisplatin FOLFILI: fluorouracil, folinic acid, irinotecan 5-FU: 5-Fluorouracil.

Fig. 1 .
Fig. 1.(a) EGD reexamination revealed a mass with a central ulceration at the lesser curvature extending from the gastric angle to antrum.(b) CT scans showed wall thickening with contrast effect on the anterior wall of the gastric lesser curvature and no clear distant metastases were observed.

Fig. 2 .
Fig. 2. H.E staining showing polygonal tumor cells forming clear and abundant eosinophilic cytoplasm, separated by sinusoidal capillaries, and trabecular and intestinal-like structures (a) and there is intravenous tumor thrombus at the proximal resection (b).Immunohistochemical staining of tumor cells are broadly positive for AFP (c), SALL-4(d), glypican-3(e).
* Corresponding author at: Department of Surgery, Onomichi General

Table 1
Review of cases of HAS with R0 resection and chemotherapy.