Molecular pathological research is rapidly advancing, and new disease entities that are based on molecular pathological findings have emerged. For example, disease entities that resemble well-differentiated neuroendocrine tumors, such as pseudoendocrine sarcoma, mesenchymal neoplasms with GLI1 gene alterations described as “distinctive nested glomoid neoplasm,” gastroblastoma, and plexiform fibromyxoma have been reported (1–7). Gastroblastoma is a distinctive biphasic stomach tumor that shows epithelioid or spindle cells and harbors the MALAT::GLI1 fusion gene (5). Pseudoendocrine sarcoma is a recently recognized entity among soft tissue sarcomas, characterized by its close resemblance to well-differentiated neuroendocrine tumors, but lacking epithelial/neuroendocrine differentiation by immunohistochemistry (IHC). Additionally, nearly all cases exhibit aberrant nuclear accumulation of β-catenin caused by the secondary activating hot spot CTNNB1 mutations (1). These lesions commonly occur in deep soft tissues (1–4). These entities are morphologically similar to well-differentiated neuroendocrine tumors, which often makes their diagnosis difficult. Herein, we report a unique case of a gastric submucosal tumor that demonstrated strong expression of monoclonal antibodies directed against keratins in the absence of neuroendocrine differentiation by IHC. However, this case did not fit any of these criteria, and we report it as a gastric submucosal neoplasm with CTNNB1 mutation, showing GLI1 overexpression and epithelial differentiation.

Gastric mesenchymal tumors are rare, with gastrointestinal stromal tumors, schwannomas, and leiomyomas being the most common. Based on the histological features observed in the initial biopsy, a diagnosis of a well-differentiated neuroendocrine tumor was considered; however, the IHC findings were not fully supportive. Gastric neuroendocrine neoplasms typically exhibit positive immunohistochemical staining for chromogranin A, synaptophysin, and INSM-1. In contrast, IHC findings suggested the possibility of gastroblastoma (5). However, gastroblastomas, similar to synovial sarcomas, usually exhibit a biphasic pattern characterized by a mixture of spindle cells and nests of epithelioid cells with abundant eosinophilic cytoplasm. These features were not observed in the present case. In addition, RT-PCR, FISH, and RNA sequencing failed to identify the presence of GLI1 gene rearrangements, MALAT1::GLI1 fusion, PTCH1::GLI1 fusion, or an EWSR1-CTBP1, recently identified in a patient with Wiskott-Aldrich syndrome (6, 8). Therefore, a diagnosis of gastroblastoma was excluded. The next possibility was a pseudoendocrine sarcoma. CTNNB1 mutation and nuclear expression for β-catenin IHC are consistent with pseudoendocrine sarcoma; however, these sarcomas occur commonly in the truncal locations such as the soft tissues of the vertebral body region and posterior head (1), so the site, in this case, did not fit pseudoendocrine sarcoma. In addition, short spindle cells arranged in tight nests were observed within a fibromyxoid stromal background that did not fit pseudoendocrine sarcoma. The case also showed focal and weak staining expression of GLI1 on IHC and monoclonal antibodies directed against keratins, such as CAM5.2 and AE1/AE3, although prior studies have not reported any positive staining for monoclonal antibodies directed against keratins and GLI1 on IHC (1, 2, 9). Based on these findings, the diagnosis of pseudoendocrine sarcoma was excluded.

The presence of the CTNNB1 mutation and the morphological similarity in this case may raise the possibility of a solid pseudopapillary neoplasm or Sertoli-like neoplasm, such as a Sertoli cell tumor of the testis. However, ectopic pancreatic tissue was not observed in the present case. Furthermore, the absence of a history of gonadal systemic tumors and no abnormalities in the gonads on PET-CT ruled out this possibility. However, the overexpression of hormone receptors such as ER, PgR, and AR in this case remains puzzling.

The possibility of a mesenchymal neoplasm with GLI1 gene alterations was raised because of GLI1 mRNA and protein overexpression (7). Recent studies have highlighted the morphological similarities between well-differentiated neuroendocrine tumors and soft tissue sarcomas with GLI1 gene alterations described as “distinctive nested glomoid neoplasm” (1, 7, 10, 11). However, it was excluded because of the absence of GLI1 fusion and the presence of the CTNNB1 mutation. Furthermore, irregular fibrous septa, lobular growth patterns, a prominent capillary network, or lobules protruding into vascular lumina beneath intact endothelium are frequently seen in distinctive nested glomoid neoplasms, but were not observed in this case. A study by Parrack et al. reported that GLI1 IHC was highly sensitive (91.3%) and specific (98.0%) for mesenchymal tumors with driver GLI1 alterations among morphological mimics (9). However, in this case, GLI1 IHC was focally and weakly positive rather than diffusely and strongly positive, which does not positively support a GLI1-altered mesenchymal neoplasm.

Furthermore, the strong and diffuse cytokeratin expression in this case seemed unusual for a GLI1-altered mesenchymal neoplasm (12). Since this case does not fit the disease concepts reported to date, we report it as “gastric submucosal neoplasm with CTNNB1 mutation showing GLI1 overexpression and epithelial differentiation.”

Regarding the prognosis of this case, the patient was followed up for almost 5 years without any treatment before undergoing surgery, during which the tumor size remained relatively stable. The MIB-1 proliferation index in the surgical specimen was approximately 5%, and the patient survived for 2 years without any evidence of recurrence or metastasis after surgery. Gastroendoscopy has been performed every year after surgery, and no new lesions are observed. These outcomes show the slow growth and low-grade nature of this tumor. This case report provides new insights into the clinicopathological characteristics of this disease.