A case of multiple gastric adenocarcinoma of fundic gland type accidentally found by additional gastrectomy following endoscopic submucosal dissection

Abstract

An octogenarian male underwent upper gastrointestinal (UGI) endoscopy for an annual surveillance program, which identified a 12 mm type 0-IIa lesion on the posterior wall of the gastric fornix. An endoscopic biopsy was performed, raising suspicion for malignancy. Subsequent endoscopic submucosal dissection (ESD) was conducted, and the final histopathological diagnosis confirmed fundic gland-type gastric adenocarcinoma. The tumor exhibited submucosal invasion to a depth of 1000 μm. No evidence of vascular invasion or residual malignant cells at the resection margins was observed. The patient decided to undergo additional proximal gastrectomy to rule out lymph node metastasis. Laparoscopic proximal gastrectomy was performed, and histopathological evaluation revealed no residual carcinoma at the ESD scar and no evidence of lymph node involvement. However, ten additional lesions of fundic gland-type gastric adenocarcinoma were identified, two of which demonstrated submucosal invasion. Biannual follow-up with endoscopy and contrast-enhanced computed tomography has been performed postoperatively. The patient has remained free of recurrence for three years.

Introduction

Gastric adenocarcinoma of the fundic gland (GA-FG), first described by Ueyama et al., is characterized as gastric adenocarcinoma with chief cell differentiation (GA-CCD). It is primarily composed of highly differentiated columnar cells, predominantly resembling chief cells, mimicking the cellular architecture of normal fundic glands [1–3]. Notably, the superficial regions tend to preserve the foveolar epithelium, while the deeper regions exhibit irregularly branched and dilated glandular structures.

Several prior studies have referred to these lesions as “oxyntic gland polyp/adenoma,” “chief cell-predominant gastric polyps,” or “oxyntic gland adenoma (OGA),” considering them conceptually benign entities [4–6]. However, the biological malignancy and clinicopathological behavior of this rare gastric epithelial neoplasm remain subjects of ongoing investigation. Reports of multicentric GA-FG are exceedingly rare. In the present case, a total of eleven GA-FG lesions were identified, three of which demonstrated submucosal invasion. Notably, two of these lesions, discovered incidentally during surgery, were covered by histologically normal foveolar epithelium.

Herein, we present a rare case of multiple GA-FG lesions—eleven in total—incidentally detected following additional gastrectomy performed after endoscopic submucosal dissection (ESD) of an elevated lesion located at the gastric fornix.

Case presentation

An elderly male in his 80 s, with a medical history of diabetes mellitus and hypertension, underwent upper gastrointestinal endoscopy as part of routine annual screening. He was asymptomatic at the time of examination. A 12 mm type 0-IIa lesion was detected on the posterior wall of the fornix (Fig. 1A). Narrow-band imaging revealed an irregular microvascular and microsurface pattern (Fig. 1B). Texture enhancement imaging with indigo carmine dye highlighted the elevated lesion (Fig. 1C). Multiple fundic gland polyps were observed extending from the fornix to the greater curvature of the gastric body. A biopsy of the lesion raised suspicion for malignancy, prompting endoscopic submucosal dissection (ESD) (Fig. 1D). Histopathological analysis confirmed GA-FG (Fig. 1E) with submucosal invasion up to 1000 μm in depth (Fig. 1F). The tumor showed slightly irregular branching ducts with mildly enlarged round nuclei and was diagnosed as adenocarcinoma with low-grade atypia. To prevent disease recurrence, the patient decided to undergo radical gastrectomy. Laparoscopic proximal gastrectomy was subsequently performed. Macroscopic inspection of the resected specimen revealed no additional dysplastic lesions (Fig. 2A), and the postoperative course was uneventful. Unexpectedly, histopathological evaluation identified ten additional GA-FG lesions (Fig. 2B), all of which, including two with submucosal invasion, were covered by intact foveolar epithelium (Figs. 3A–3D). Gastric adenocarcinoma mimicking fundic gland morphology was observed within the submucosal layers (Figs. 3E and 3F). Immunohistochemical analysis was undertaken to further characterize the neoplasm. The primary elevated tumor demonstrated only surface-layer positivity for MUC5AC on foveolar epithelium-like cells (Fig. 4B), along with diffuse positivity for MUC6 (Fig. 4C), Pepsinogen (Fig. 4D), MIB1 (Fig. 4E), and H^ + /K^ + -ATPase (Fig. 4F), as shown by HE staining (Fig. 4A).

Fig. 1.

Primary elevated lesion at the fornix. A A picture of the elevated tumor at the posterior wall of the fornix captured by endoscopy is shown. B A picture of the elevated tumor with narrow band imaging. C A picture of the tumor with a dye of indigo carmine. D Macroscopic view of resected specimen of 0-IIa lesion of 15 mm in size, fixed by formalin. E Hematoxylin and eosin staining showed that the tumors surrounded by red line had clear demarcation from the surrounding fundus glands and an irregular glandular structure. A bar is 2000 μm. F The tumor had invaded the submucosal layer, measured by yellow bar of 1000 μm. A bar is 1000 μm

Fig. 2.

Macroscopic findings of resected specimen. A A resected specimen of proximal stomach. Multiple fundic polyps are seen. B Mapping of multiple GAFGs without elevated lesion on resected specimen fixed by formalin is shown after the careful extended pathological examination of whole area of specimen. Red bars indicate GAFGs. Light green bar indicates ESD scar. White bars show foreign body reactions

Fig. 3.

Microscopic findings of multiple GAFGs incidentally found after proximal gastrectomy. A–D Multiple GAFGs existed without being exposed to intracolumnar surface and covered by normal epithelium. E and F Fundic gland-like cells are located at the bottom of the normal epithelium. Bars are 200 μm (E) and 50 μm (F)

Fig. 4.

Immunohistochemical results of main elevated GAFG. A HE staining of main tumor. Immunohistochemical staining; B MUC5AC, C MUC6, D Pepsinogen, E Ki-67 Labeling Index = 13%, E H + /K + -ATPase. Bars are 200 μm (A–C) and 50 μm (D–F)

No evidence of vascular invasion or lymph node metastasis was identified. The patient has since undergone biannual surveillance with upper gastrointestinal endoscopy and contrast-enhanced computed tomography. No recurrence or emergence of new GA-FG lesions has been observed over a follow-up period of three years.

Discussion

Ueyama et al. proposed a novel histological subtype of gastric carcinoma exhibiting differentiation toward fundic glands, designated as gastric adenocarcinoma of the fundic gland type (GA-FG) [1–3]. Although GA-FG is typically associated with non-atrophic gastric mucosa in Helicobacter pylori-negative individuals, occurrences have also been documented in patients with a history of H. pylori eradication or active infection [2, 7]. GA-FG remains a rare entity, with a reported prevalence ranging from 0.98 to 1.6% among all gastric cancer cases [7, 8]. This neoplasm predominantly arises in the upper gastric region, originating from the deep layer of morphologically intact fundic glands [7]. The average age of onset is 67.7 years in Japan, with most patients aged between 60 and 70 years [9]. A male predominance has been observed, with a global male-to-female ratio of 2.2, and a ratio of 1.4 reported in Japan [9]. This disease may have a sex bias, with a worldwide male-to-female ratio of 2.2 versus 1.4 in Japan [9].

Endoscopically, GA-FG is characterized by the following features: (1) a submucosal tumor-like appearance, which may be protruding, flat, or depressed; (2) pale, whitish, or reddish discoloration with a soft texture; (3) dilated, branching vasculature; and (4) an absence of atrophic changes, intestinal metaplasia, or chronic gastritis [9]. Although the tumor size is typically small, submucosal infiltration is frequently observed. Given the limited reports of vascular invasion or lymph node metastasis, GA-FG is considered a neoplasm with low-grade malignant potential. A 12-year longitudinal observation of a GA-FG case showed no morphological progression of the tumor [10]. Nonetheless, a case of GA-FG with poorly differentiated components and lymph node metastases demonstrated histologic transformation into an infiltrative gastric-type adenocarcinoma with foveolar differentiation, confirmed by diffuse MUC5AC expression [11].

Multiple GA-FG lesions have been reported in a limited number of cases. A literature review identified three previously reported cases of multiple GA-FGs [12–14]. Including the present case, clinical characteristics of four patients are summarized in Table 1. A notable finding across these cases is the high frequency of submucosal infiltration, even in small lesions. No instances of lymph node metastasis were reported, and only one lesion exhibited vascular invasion.

Table 1.

Reported cases with multiple GA-FG

Year	Age	Gender	Tumor number	Tumor size# (mm)	Macroscopic shape	Color	Deapth#(μm)	ly§	v†	Reference articles
2018	78	Male	2	7	Protruding	Yellowish	120 (sm)	(−)	(−)	11
2018	71	Male	3	6	Depressed	Faded	200 (sm)	(−)	(+)	12
2019	46	Female	3	6	Elevated (2)	Redness	500 (sm)	(−)	(−)	13
					Flat (1)	NA
2024	80	Male	11	15	Elevated (1)	Faded (1)	1000 (sm)	(−)	(−)	Current case
					Flat (10)	Unknown

^#Maximum value

^§Pathological lyphatic invasion

^†Pathological vascular invasion

Immunohistochemically, GA-FG typically expresses Pepsinogen I, H^ + /K^ + -ATPase, and MUC6, but lacks MUC5AC expression. In contrast, gastric adenocarcinomas exhibiting both fundic gland-like and mucous foveolar features—referred to as GA-FGM (gastric adenocarcinoma of fundic gland mucosa type)—demonstrate MUC5AC positivity, particularly in foveolar-like cells [3]. In the current case, the immunohistochemical staining pattern suggested a diagnosis of GA-FGM. According to the subclassification of GA-FGM, Type 2 tumors exhibit MUC5AC positivity in both superficial and deep layers and are associated with a more aggressive phenotype. Type 1 lesions, which display MUC5AC positivity restricted to the superficial layer, correspond to the phenotype observed in our patient. Type 3 is defined by MUC5AC expression limited to the deeper layers [3].

Given the possibility of occult, multifocal lesions in the remnant stomach, the decision regarding additional treatment following proximal gastrectomy is clinically significant. Considering the patient's advanced age, prophylactic completion gastrectomy may constitute overtreatment. Optimal therapeutic strategies should be guided by the accumulation of clinical evidence in the future. Although GA-FG generally exhibits low malignant potential compared to conventional gastric adenocarcinomas, Type 2 GA-FGM may represent a more aggressive variant. In this case, the main lesion was consistent with Type 1 GA-FGM, based on only superficial MUC5AC expression. Taking into account these findings, we recommended careful follow-up with periodic endoscopic surveillance and contrast-enhanced CT imaging. The patient consented to our suggestion.

Conclusion

We reported an exceptionally rare case of multiple GA-FG lesions, eleven in total, discovered through additional proximal gastrectomy following endoscopic submucosal dissection of an elevated gastric lesion. Despite submucosal invasion in several foci, no lymph node metastases or vascular invasion were identified. The patient has undergone biannual endoscopic evaluations and annual contrast-enhanced CT imaging, with no evidence of recurrence observed over a three-year follow-up period.

Author contributions

HT and HO, drafting the manuscript and final approval; HN, MT, AO, DK, and HK, acquisition of clinical information and discussion of the content; KH, TM, HB, and TH, critical revision of the manuscript; HS; supervision and final approval.

Funding

None.

Data availability

Research data are not shared.

Declarations

Conflict of interest

The authors have no conflict of interest.

Ethical approval

All procedures followed have been performed in accordance with the ethical standards laid down in the Declaration of Helsinki and its subsequent amendments.

Informed consent

Informed consent was obtained from the patient whose case details appear in this manuscript.