Gastric submucosal neoplasm with CTNNB1 mutation showing GLI1 overexpression and epithelial differentiation

Karin Ashizawa ¹ Tsuyoshi Saito ^1* Yukinori Yube ² Shinji Mine ² Tetsu Fukunaga ² Cristina R Antonescu ³ Takashi Yao ¹

• ¹ Human Pathology, Juntendo University, Bunkyō, Japan
• ² Upper Gastroenterological Surgery, Juntendo University, Bunkyō, Japan
• ³ Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States

New disease entities have been emerging based on molecular pathological findings, such as pseudoendocrine sarcoma and mesenchymal neoplasm with GLI1 gene alterations, which resemble well-differentiated neuroendocrine tumors. We report a unique case of a gastric submucosal neoplasm of approximately 1.5cm in size with CTNNB1 mutation showing GLI1 overexpression and epithelial differentiation in a 66-year-old man. It was incidentally identified by routine health screening, and was a slowly growing tumor. Macroscopically, it was a slightly protruded tumor into the mucosa, and was primarily located from the submucosa to the muscularis propria. It was a well-defined lesion measured approximately 20mm, and was almost stable during almost 5 years after initial identification of the tumor. Uniform round-to-epithelioid cells arranged in solid trabeculae with a microtubular/acinar appearance were seen microscopically. Occasional mitotic figures were noted, but no necrosis was observed. Immunohistochemistry (IHC) demonstrated diffuse expression of pan-cytokeratin, CD10, and CD56 without neuroendocrine markers (chromogranin A, synaptophysin, and INSM1). Molecular analysis confirmed the presence of a hot spot CTNNB1 mutation (S33C), supported by diffuse βcatenin nuclear expression by IHC. Further molecular investigations revealed the absence of GLI1 gene rearrangements, GLI1 amplification, and other fusions. Several differential diagnoses were considered; however, none adequately fit the criteria. The patient remained disease-free for 24 months postoperatively without further adjuvant therapy.