Eight Chinese patients diagnosed with GA-FG who visited the Affiliated Hospital of Zunyi Medical University during a 3-year-period from 2017 to 2019 were included in the study. Patient age ranged from 48-80 years, with an average age of 65 years. There were five female and three male patients. Available clinical information (including gender, age, medication history, and site and size of the lesion), endoscopic features [including shape and microvascular pattern (MVP)], pathological appearance (including histological and immunohistochemical data), and follow-up data were assessed.
Five of the patients presented with symptoms of gastroesophageal reflux, one presented with bloating, and two with abdominal pain that prompted endoscopic examination. Most of them were on irregular medications. Acid-suppression treatment included the use of a proton pump inhibitor (PPI) (n = 4) and histamine (H2) receptor antagonist (n = 1). The remaining patients had no history of medication. History of past illness revealed that three patients had chronic non-atrophic gastritis, but did not receive standard treatment. There was no personal and family history bearing upon the case. There was no physical examination available. None of the eight cases showed serum anti-H. pylori antibody in the urea breath test.
Clinicopathological details of all patients are summarized in Tables 1 and 2. The lesions were located in the upper (n = 7) and middle third (n = 1) of the stomach. Histopathological reviews were conducted by three pathologists based on the following items: histological subcategories (chief cell predominant, parietal cell predominant, and mixed phenotype), architectural patterns, presence of cytonuclear atypia, depth involvement, and mucosal atrophy or intestinal metaplasia of adjacent mucosa. Architectural patterns noted included the presence of clustered and or solid glands with or without well-formed glands, anastomosing cords, dilated glands, complex glands with multiple layers of cells, and cribriform glands10. MUC2, MUC5, MUC6, P53, CDX2, Ki67, SYN, CD56, CGA, β-catenin, and pepsinogen-I were used as immunohistochemical markers and immunohistochemical staining was performed as per the manufacturer’s instructions.
Prior to endoscopic submucosal dissection (ESD), upper gastrointestinal endoscopy was performed using narrow-band imaging using magnifying endoscopy (NBI-ME) in addition to the conventional white-light endoscopy. All eight biopsy specimens were used for histological diagnosis. Six cases were macroscopically identified as type 0–IIa (superficial elevated type) and two were identified as type 0–IIb or c (superficial flat type or depression, respectively) (Figure 1A). NBI-ME showed irregular MVP with dilated vessels in 4 cases (Figure 1B) and regular MVP in 4 cases. Endoscopic examination prior to pathological diagnosis was indicative of carcinoid, GA-FG, adenocarcinoma, and adenoma in two cases each.
A pathological biopsy was performed in all cases. Four cases were diagnosed as GA-FG and the remaining four as oxyntic gland adenoma owing to limitations in the number of submucosae for evaluation and the presence of well-differentiated oxyntic glands. ESD-resected specimens were subjected to conventional histological testing and immunohistochemical staining. Grossly, they were described as solitary and ranged in size from 4–12 mm (mean, 6 mm) (Figure 2A, 2B).
Histologically, all tumors arose from the deep mucosa layer with an infiltrative growth pattern and most of the tumor surface was covered with normal foveolar epithelium (Figure 3A). Six of the lesions extended into the submucosa and the depth of invasion ranged from 50–600 µm (average, 182 µm). The remaining cases showed partial invasion into the mucosal muscle. In all eight present cases, chief cells were the predominant cell type. Most tumors consisted of well-formed glands of oxyntic epithelial cells; few tumor cells consisted of clustered glands, irregular anastomosing cords, and cribriform glands (Figure 3B). Tumor cells showed mild atypia (Figure 3C). Atrophy and intestinal metaplasia were observed in the background of one case (Figure 3D, case 5). In all cases, lymphatic or venous invasion and latera or vertical margin invasion were distinctly absent.
Immunohistochemical examination revealed diffuse positivity for MUC6 and pepsinogen-I for all tumors (100%) (Figure 4A, 4B). In contrast, MUC2, MUC5, and CDX2 expression were negative in all cases. However, foveolar cells showed MUC5 positivity, which indicated the presence of intact foveolar epithelium (Figure 5A). MUC2 positivity was observed in the glands with intestinal metaplasia (Figure 5B). Consistent with morphology, CDX2 and P53 were not overexpressed and the Ki-67 labeling index was low (< 2%, with a minimum of 1,000 evaluated cells). It is noteworthy that synaptophysin and CD56 positivity was observed in all eight cases (Figure 5C, 5D), while chromogranin A positivity was scattered (two of eight). Membrane staining of β-catenin was observed with no nuclear accumulation in any of the cases.
FINAL DIAGNOSIS
All cases were diagnosed as gastric adenocarcinoma of the fundic gland type (chief cell-predominant) on the basis of endoscopy, morphology, and immunohistochemical features.
TREATMENT
After the lesions were completely removed using ESD, patients were provided appropriate symptomatic therapy to suppress acid secretion and hemostasis, and to protect the gastric mucosa.
OUTCOME AND FOLLOW-UP
Follow-up examinations were performed for all patients after ESD until recently. Clinical follow-up information was available for all (100%) patients and ranged from 5–33 months (mean, 17 months). Disease progression or metastases were not reported.