A 60-year-old man presented with a mass in the upper abdomen. Blood analysis revealed slight elevations of aspartate aminotransferase (AST, 144 IU/L) and alanine aminotransferase (ALT, 101 IU/L) levels. Serum tumor marker studies showed elevated levels of carcinoembryonic antigen (CEA, 49.3 ng/mL; reference range, < 5.3 ng/mL), carbohydrate antigen 19-9 (CA19-9, 45.0 U/mL; reference range, < 35 U/mL), and alpha-fetoprotein (AFP, 173.2 ng/mL; reference range, < 10 n/mL). Gastroscopy revealed an ulcerative mass measuring 40–50 mm in size on the greater curvature corpus of the stomach (Fig. 1a). Histopathological examination of a biopsy specimen showed moderately differentiated tubular adenocarcinoma and strong (3+) HER2 positivity on immunohistochemical staining (Fig. 1b, c). Enhanced computed tomography revealed wall thickening from the upper to middle stomach and increasing ambient fat concentration. In addition, there were ring-enhanced liver metastases (100 mm and 105 mm in diameter) in the left lobe of the liver; marked enlargement was observed in the left gastric artery and celiac artery lymph nodes (Fig. 2a, b). 18F-fluorodeoxyglucose positron emission tomography/computed tomography showed abnormal accumulations of fluorodeoxyglucose at celiac artery lymph nodes, tumors of the upper stomach, and in the left lobe of the liver. Thus, the patient was diagnosed with advanced gastric cancer, T4a(SE) N2 M1(HEP), stage IV.
Because of the HER2-positive immunohistochemical staining results, combination chemotherapy was initiated: capecitabine (2000 mg/m2 orally, days 1–14), cisplatin (80 mg/m2 intravenously, day 1), and T-mab (6 mg/kg intravenously, day 1). After six courses of chemotherapy, tumor markers, AST, and ALT levels were decreased (CEA, 10.9 ng/mL; CA19-9, 16.3 U/mL; AFP, 72.6 ng/mL; AST 43 IU/L; ALT, 16 IU/L). Computed tomography imaging revealed an extremely shrunken hepatic lesion and lymph nodes (Fig. 2c, d). After seven courses of chemotherapy, the patient experienced severe appetite loss and refused further chemotherapy.
Because laparoscopic exploration did not reveal any unresectable factors, such as peritoneal dissemination or positive cytology, the patient underwent open total gastrectomy (D2 lymph node dissection), distal pancreatosplenectomy, and extended left hepatic lobectomy as a conversion surgery with curative intent. The patient was discharged at 12 days postoperatively with an uneventful postoperative course.
The resected specimen revealed a type 3 tumor on the upper corpus and the greater curvature of the stomach, which measured 85 × 40 mm. The pathological examination revealed that the tumor involved subserosa layer and 2 of 47 lymph nodes were positive for metastasis. Histopathological examination showed that it was composed of enriched solid and small nested growths of high nuclear cytoplastic ratio tumor cells with necrosis and fibrosis; these cells had atypical enlarged hyperchromatic nuclei. In addition, the tumor was composed of adenocarcinoma cells that exhibited tubular growth with cribriform structure (Fig. 3a, b). Immunohistological analysis demonstrated that the tumor cells were focally positive for synaptophysin, chromogranin A, and carcinoembryonic antigen (Fig. 4). The final pathological diagnosis was MANEC. The liver tumors were white solid nodules that measured 66 × 41 × 71 mm in segment 3, 23 × 22 × 17 mm in segments 4 and 8, and 17 × 14 × 15 mm and 23 × 20 × 20 mm in segment 4 of the liver. The tumors were pathologically compatible with metastases from the gastric cancer. The therapeutic effects of chemotherapy were grade 1a. The immunohistochemical HER2 scores were 1 for the primary gastric cancer and 0 for the liver metastases (Fig. 3c, d).
After the operation, the patient began to take tegafur-gimeracil-oteracil potassium (S-1; 100 mg/day orally) as adjuvant chemotherapy; we then reduced the dose of S-1 to 80 mg/day beginning in the third course because of the development of grade 1 diarrhea, grade 2 neutropenia, grade 3 thrombocytopenia, and grade 3 terminal ileal inflammation. At 3 months postoperatively, computed tomography imaging revealed four scattered liver metastases, the largest of which was 47 mm in diameter. The patient discontinued adjuvant chemotherapy with S-1 and began chemotherapy with paclitaxel (80 mg/m2). After two courses of chemotherapy, computed tomography imaging revealed multiple progressive liver metastases. One month after the end of chemotherapy, the patient exhibited consciousness disturbance due to hepatic disfunction; he died 6 months postoperatively. The autopsy was not performed because the consent was not obtained from the family. We re-evaluated the immunohistochemical status of endoscopic biopsy specimens before surgery; these were negative for synaptophysin and partially positive for chromogranin A and CD56 (Fig. 5).