Gastric epithelial neoplasm of fundic-gland mucosa lineage: representative of the low atypia differentiated gastric tumor and Ki67 may help in their identification

Abstract

Background: Gastric epithelial neoplasm of the fundic-gland mucosa lineages (GEN-FGMLs) are rare forms of gastric tumors that encompass oxyntic gland adenoma (OGA), gastric adenocarcinoma of the fundic-gland type (GA-FG), and gastric adenocarcinoma of the fundic-gland mucosa type (GA-FGM). There is no consensus on the cause, classification, and clinicopathological features of GEN-FGMLs, and misdiagnosis is common because of similarities in symptoms.

Methods: 37 cases diagnosed with GEN-FGMLs were included in this study. H&E-stained slides were reviewed and clinicopathological parameters were recorded. Immunohistochemical staining was conducted for MUC2, MUC5AC, MUC6, CD10, CD56, synaptophysin, chromograninA, p53, Ki67, pepsinogen-I, H⁺/K⁺-ATPase and Desmin.

Results: The patients' ages ranged from 42 to 79 years, with a median age of 60. 17 were male and 20 were female. Morphologically, 19 OGAs, 16 GA-FGs, and two GA-FGMs were identified. Histopathological similarities exist between OGA, GA-FG, and GA-FGM. The tumors demonstrated well-formed glands, expanding with dense growth patterns comprising pale, blue-grey columnar cells with mild nuclear atypia. These cells resembled fundic gland cells. None of the OGA invaded the submucosal layer. The normal gastric pit epithelium covered the entire surface of the OGA and GA-FG, but the dysplasia pit epithelium covered the GA-FGM. Non-atrophic gastritis was observed in more than half of the background mucosa. All cases were diffusely positive for MUC6 and pepsinogen-I on immunohistochemistry. H⁺/K⁺-ATPase staining was negative or showed a scattered pattern in most cases. MUC5AC was expressed on the surface of GA-FGMs. p53 was focally expressed and the Ki67 index was low (1%-20%). Compared with OGA, GA-FG and GA-FGM were more prominent in the macroscopic view (p < 0.05) and had larger sizes (p < 0.0001). Additionally, GA-FG and GA-FGM exhibited higher Ki67 indices than OGA (p < 0.0001). Specimens with Ki-67 proliferation indices >2.5% and size >4.5 mm are more likely to be diagnosed with GA-FG and GA-FGM than OGA.

Conclusion: GEN-FGMLs are group of well-differentiated gastric tumors with favourable biological behaviours, low cellular atypia, and low proliferation. Immunohistochemistry is critical for confirming diagnosis. Compared with OGA, GA-FG and GA-FGM have larger sizes and higher Ki67 proliferation indices, indicating that they play a critical role in the identification of GEN-FGML. Pathologists and endoscopists should be cautious to prevent misdiagnosis and overtreatment, especially in biopsy specimens.

Keywords: gastric adenocarcinoma of fundic-gland mucosa type; gastric adenocarcinoma of fundic-gland type; gastric cancer; low-grade differentiated gastric tumors; oxyntic gland adenoma.

FIGURE 1

Representative images of a 53-year-old male patient diagnosed with OGA. (A): The image of NBI shows fundus mucosa observed as a flat lesion in the macroscopic view. (B): The lesion was clearly defined on the mucosa layer. The lesion covered normal gastric pit epithelium and glands exhibited branching, expanding arrangement (40×). (C): The glands were composed of columnar cells with mild nuclear atypia, similar to fundic gland cells. The nuclei were slightly enlarged (400×).

FIGURE 2

Representative images of a 63-year-old female patient diagnosed with GA-FG: 0-IIb, Tub1>tub2 (SM1), Ly0, V0, UL (−), pHM0, pVM0. (A): The image of NBI shows background fundus mucosa without H. pylori infection and non-atrophic gastritis. The 0–IIb lesion had a blurred border with irregularly arranged marginal crypt epithelium with asymmetric distribution. The lesion consisted of microvessels with dendritic vasculature. (B): Macroscopic findings of the resected specimen showing a protruding submucosal lesion. (C): The lesion was clearly defined and infiltrated into the submucosa. (D) The lesion covered normal gastric pit epithelium and glands and exhibited branching, expanding arrangement, and fusion (100×). (E): The tumors exhibited mild cellular and structural atypia with well-formed glands, similar to fundic gland cells (200×). (F): The glands were composed of pale grey-blue, basophilic columnar cells with mild nuclear atypia. The nuclei had hyperchromatic chromatin and were slightly enlarged (400×). (G–L): Immunohistochemical analysis. (G) Desmin showed carcinoma invasion of the submucosal layer (100×). Carcinoma was diffusely positivity for MUC6 (H, 400×), pepsinogen-I (I, 400×), and Syn (K, 400×), focally positivity for H+/K + -ATPase (J, 400×), and Ki67 index was 3% (L, 400×).

FIGURE 3

Representative images of a 71-year-old female patient diagnosed with GA-FGM: 0-IIa, Tub1>tub2 (SM2), Ly0, V0, UL (−), pHM0, and pVM0. (A): Conventional endoscopy revealed a smooth, reddish lesion in the gastric fundus with distinct borders. The background mucosa did not show H. pylori infection and non-atrophic gastritis. The lesion exhibited significant changes in microvascular and microsurface patterns. The marginal crypt epithelium had a complex ripple-like pattern that was wider and irregularly arranged compared to that of the background mucosa. (B,C): Macroscopic findings of the resected specimen showing a protruding lesion. (C,D): The lesion was well-defined and infiltrated into the submucosa (20×). (E): The pit epithelium exhibited cellular atypia, and glands exhibited branching, expanding arrangement, and fusion (400×). (F): The tumors exhibited marked cellular and structural atypia. The glands were composed of pale grey-blue and basophilic columnar cells (40×). (G): The pit epithelium exhibited obvious cellular and structural atypia (400×). (H–L): Immunohistochemical analysis (400×). Carcinoma was diffusely positive for MUC6 (H) and pepsinogen-I (I). The pit epithelium was positive for MUCAC (J) and diffusely positive for Syn (K), and Ki67 index was 15% (L).

FIGURE 4

ROC analysis to assess the specificity and sensitivity of Ki-67 and Size to differentiate between OGA GA-FG and GA-FGM in GA-FGML.