Introduction

Subepithelial lesions (SELs) are found in approximately 1% to 2% of all esophagogastroduodenoscopy (EGD) procedures [1]. The stomach is the most common site of occurrence, but SELs can also be identified in the esophagus and duodenum. Most SELs identified during EGD are benign at presentation; however, several studies have reported that less than 15% display malignant features [2]. Frequent types of SEL include gastrointestinal stromal tumor, leiomyoma, lipoma, ectopic pancreas, neuroendocrine tumor, and inflammatory fibroid lesion.

Gastric cancer primarily arises from the epithelial cells of the gastric mucosa and typically does not display characteristics similar to SELs. However, in rare instances, SEL-like gastric cancer may be categorized within the spectrum of gastric SELs [3]. Consequently, when SEL-like gastric cancer is identified during routine EGD, it is challenging to diagnose it as gastric cancer at the initial stage.

A 74-year-old male patient was diagnosed with gastric cancer in the exact location where gastric SEL had been previously identified 10 years earlier during a routine health checkup EGD. In this case report, we detail the diagnostic steps and clinical implications of SEL-like gastric cancer, including gastric cancer with lymphoid stroma (GCLS) that developed over a period of 10 years.

Case

Ethical statements: This study was approved by the Institutional Review Board (IRB) of Kosin University Gospel Hospital (IRB No. 2025-07-022) and the need for informed consent was waived.

A 64-year-old male patient was referred to our hospital after a gastric SEL was detected at the cardia during a routine health checkup EGD. For further assessment, he underwent EGD, gastric endoscopic ultrasonography (EUS), and abdominal computed tomography (CT). EGD at our institution identified a round, protruding lesion approximately 15×15 mm in size with a normal-appearing mucosal surface overlying the cardia (Fig. 1A). Biopsy of the gastric lesion yielded a pathological diagnosis of “Mature squamous epithelium with negative for malignancy.” EUS demonstrated a well-defined, bumpy, hypoechoic, homogeneous lesion measuring 12.7×12.0 mm arising from the muscularis propria layer (Fig. 1B). Abdominal CT identified a homogeneous mass-like lesion at the cardia, with no evidence of lymph node enlargement in the abdominopelvic region (Fig. 1C). Because the gastric SEL was less than 2 cm and the patient was asymptomatic, we opted for follow-up in consultation with the patient.

He was advised to undergo regular endoscopic surveillance; nonetheless, he did not maintain consistent attendance at scheduled outpatient follow-up visits. Several years later, in January 2018, he returned to our hospital for a reassessment of the gastric SEL. Both EGD and gastric EUS were repeated. EGD visualized a gastric SEL without any substantial changes in comparison to his prior examination (Fig. 2A). The pathological finding remained “Mature squamous epithelium with negative for malignancy.” EUS showed a bumpy, hypoechoic, homogeneous, well-circumscribed lesion, now measuring 16.2×13.1 mm and still arising from the muscularis propria layer (Fig. 2B), representing an increase in size compared to the previous EUS. The patient was advised to undergo tissue confirmation procedures, such as EUS-guided fine needle biopsy or mucosal incision-assisted biopsy, but declined further intervention.

In December 2021, he underwent a screening EGD at a primary clinic, which resulted in a diagnosis of gastric cancer. Following this, he returned to our hospital and was hospitalized for further assessment. Upon admission, his vital signs were as follows: blood pressure, 130/80 mmHg; pulse, 80 beats per minute; respiratory rate, 20 breaths per minute; and temperature, 36.1 ℃. Physical examination, chest X-ray, and electrocardiogram revealed no abnormal findings. Laboratory test results were largely within normal limits, including a carcinoembryonic antigen level of 1.82 ng/mL (reference, 0–5.5 ng/mL) and a carbohydrate antigen 19-9 level of 7.25 U/mL (reference, 0–34.0 U/mL). EGD performed at our hospital identified a round ulcero-protruding lesion approximately 25×25 mm in size with hyperemic and friable mucosa at the cardia (Fig. 3A). Abdominal CT scan revealed an ulcero-fungating mass in the cardia, along with surrounding fat infiltration (Fig. 3B). F-18 positron emission tomography-CT scan demonstrated a localized hypermetabolic lesion in the cardia (Fig. 3C). The lesion was diagnosed as advanced gastric cancer, and a radical total gastrectomy with Roux-en-Y esophagojejunostomy was performed (Fig. 4A). The resected mass measured 5.1×4.0×1.4 cm (Fig. 4B) and showed invasion into the muscularis propria (Fig. 4C) with lymphatic involvement. No lymph node metastasis was detected among the 43 regional lymph nodes evaluated. Prominent lymphoid stroma (Fig. 4D) and Epstein-Barr virus (EBV) positivity (Fig. 4E) were observed. Immunohistochemical testing showed that the specimen was positive for p53 (Fig. 4F). The pathological stage was pT2N0M0 (pStage I) gastric adenocarcinoma, poorly differentiated and associated with extensive lymphoid stroma. He showed no evidence of cancer recurrence through April 2025.

Discussion

SELs are defined as lesions thought to originate beneath the epithelial layer, encompassing benign and malignant tumors as well as lesions due to extrinsic compression. The majority of SELs are asymptomatic, commonly identified as subepithelial protrusions covered by normal mucosa during national gastric cancer screening programs in Korea and Japan. A recent multicenter Korean study indicated that the prevalence of SELs detected during screening EGD was 1.6% (1,044 out of 65,233 participants), with the stomach being the most frequent site (63.8%) [1].

Generally, gastric SELs smaller than 1 cm that appear smooth and benign are often monitored without obtaining a tissue diagnosis. However, tissue diagnosis of gastric SELs is typically indicated under the following circumstances: (1) SELs larger than 2 cm, (2) symptomatic SELs, such as those presenting with bleeding or obstruction, (3) any size SELs with suspicious endoscopic or EUS characteristics, including ulceration, irregular margins, echogenic foci, necrotic changes, or rapid growth [4-6]. For gastric SELs measuring 1–2 cm, EUS is typically performed initially to assess whether ongoing surveillance or a tissue diagnosis is appropriate [7]. In this case, the patient was first diagnosed in 2011, at which time he was asymptomatic and the gastric SEL measured approximately 1.2 cm. Despite EUS revealing irregular margins, the lesion was considered likely benign and a decision was made to monitor over time. By 2018, the lesion had increased in size compared to 2011, and as a result, tissue diagnosis was recommended.

As previously mentioned, most SELs are benign at the time of diagnosis, with less than 15% identified as malignant [2]. SELs with malignant potential typically include high-risk gastrointestinal stromal tumor, neuroendocrine tumors, lymphoma, metastases, and glomus tumors [4]. Although not a typical SEL, SEL-like gastric cancer represents a rare subtype of gastric cancer, with an estimated prevalence ranging from approximately 0.24% to 1.27% [3]. The majority of reported SEL-like gastric cancer cases have occurred in Japan, while only a few cases have been documented in Korea. The precise pathogenesis of SEL-like gastric cancer remains unclear, but four potential mechanisms have been proposed. First, this presentation may result from pronounced lymphocytic infiltration into the tumor, characterized as lymphoepithelioma-like carcinoma or GCLS [8]. Secondly, it may be caused by abundant mucin secretion associated with mucinous adenocarcinoma [9]. Third, excessive fibrosis surrounding gastric cancer can facilitate tumor cell infiltration into the muscularis mucosae prior to reaching the lamina propria, making differentiation from SEL challenging [10,11]. A fourth mechanism involves adenocarcinoma developing from heterotopic gastric glands located in the submucosa, a phenomenon that is exceedingly rare [12].

In lymphoepithelioma-like carcinoma, also known as GCLS, large oval tumor cells with clear nuclei are observed in the lymphoid follicular spaces, possessing distinct nucleoli and abundant eosinophilic cytoplasm with indistinct cell borders. Additionally, dense lymphoid infiltration reminiscent of lymphoid tissue in a nondesmoplastic stroma, and discrete areas of glandular differentiation may be observed [13]. Significant lymphocytic infiltration occurs within the submucosal layer and lymphoid follicles develop, leading to the formation of a SEL. Due to the limited exposure of gastric cancer on the mucosal surface, diagnosis through tissue biopsy prior to treatment may be challenging [3]. The patient described in this case was EBV-positive, and over 80% of such cases are known to be associated with EBV [14]. EBV-associated gastric cancer accounts for approximately 10% of gastric cancers globally and demonstrates characteristic clinicopathological features [15]. A recent meta-analysis demonstrated that patients with EBV-positive GCLS exhibit lower mortality rates (p=0.009; 95% confidence interval, 0.15–0.77; I² = 48.6%) based on nine retrospective studies, which included 618 EBV-positive and 153 EBV-negative GCLS cases [16]. Kim et al. [17] observed that, although only 1.9% of 214 patients with EBV-associated gastric cancer exhibited heterogeneous EBV status, the EBV-positive and-negative regions displayed distinct histological patterns, immune microenvironments, and some varying genomic characteristics. Although the natural disease course of GCLS remains unclear, the 10-year disease-free interval in this patient is presumed to be associated with the generally favorable prognosis observed in EBV-positive GCLS cases. Following surgery, the patient was staged as pathological I (T2N0M0) and has remained recurrence-free under ongoing surveillance. To our knowledge, there have been very few cases reported over the past 10 years in which gastric SELs were ultimately identified as SEL-like gastric cancers, such as GCLS. This case report is distinct in that it provides an account not only of a gastric cancer presenting as a SEL, but also of the longitudinal course of gastric cancer over a 10-year period.

In conclusion, even if an incidental gastric SEL smaller than 2 cm is found, SEL-like gastric cancer remains a rare possibility; therefore, thorough evaluation of gastric SEL and diligent endoscopic follow-up are warranted in these cases.

Article information

Conflicts of interest

Won Moon is the editor-in-chief and Sung Eun Kim is an associate editor of the journal but were not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.

Funding

None.

Author contributions

Conceptualization: SEK. Data curation: BJK, SEK, KWS, HKC. Investigation: BJK, SEK. Methodology: SEK, KWS, HKC. Project administration: BJK, SEK. Resources: BJK, SEK, KWS, HKC. Software: BJK, SEK. Supervision: SEK. Validation: BJK, SEK. Writing-original draft: BJK, SEK. Writing-review and editing: BJK, SEK, SJP, MIP, WM, JHK, KJ, MHL, JWL, KWS, KHC. All authors read and approved the final manuscript.

Fig. 1.

(A) EGD demonstrating a 15×15 mm round protruding lesion with normal mucosal surface at the cardia in 2011. (B) EUS showing a round, well-defined, irregular lesion located in the muscularis propria layer in 2011. (C) Abdominal CT revealing a homogeneous mass-like lesion at the cardia, without evidence of lymph node enlargement in 2011 (C). EGD, esophagogastroduodenoscopy; EUS, endoscopic ultrasonography; CT, computed tomography.

Fig. 2.

(A) EGD demonstrating a 15×15 mm round protruding lesion with normal overlying mucosa at the cardia in 2018, with no remarkable change compared to 2011. (B) EUS showing a round, well-defined, irregular lesion in the muscularis propria layer in 2018, which remained similar in size compared with 2011. EGD, esophagogastroduodenoscopy; EUS, endoscopic ultrasonography.

Fig. 3.

(A) EGD demonstrating a 25×25 mm round ulcerated protruding lesion with hyperemic, easily friable mucosa at the cardia in 2021. (B) Abdominal CT revealing an ulcero-fungating cardiac mass with surrounding fat infiltration in 2021. (C) F-18 PET-CT demonstrating a localized hypermetabolic lesion at the cardia in 2021. EGD, esophagogastroduodenoscopy; CT, computed tomography; F-18 PET-CT, F-18 positron emission tomography-computed tomography.

Fig. 4.

(A, B) Gross appearance of the resected cancer specimen. (C) Pathological examination reveals that gastric cancer was well encapsulated and exhibited a protruding morphology, with invasion into the muscularis propria layer (H&E stain, ×40). (D) Gastric cancer demonstrated abundant lymphoid stroma (H&E stain, ×100). (E) EBV positivity was observed in the adenocarcinoma region (H&E stain, ×200). (F) The tumor demonstrated p53 positivity by immunohistochemical staining (×200). H&E, hematoxylin & eosin; EBV, Epstein-Barr virus.

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References

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