Frequent synaptophysin expression in SMARCA4-deficient undifferentiated carcinoma of the oesophagus: a diagnostic pitfall with therapeutic implications

Background SMARCA4-deficient neoplasms are aggressive tumours typically arising in the thoracic region, often responding to immunotherapy despite poor prognosis. Although rare, these tumours can also occur in the gastrointestinal tract, including the oesophagus. Given the potential for misdiagnosis, particularly when tumours present with undifferentiated morphology, this study aimed to identify key diagnostic features of SMARCA4-deficient undifferentiated carcinoma of the oesophagus (SMARCA4-deficient UC) and highlight the clinical importance of accurate diagnosis. Material and method A retrospective review of 36 oesophageal carcinoma cases with undifferentiated histology was conducted following institutional review board approval. All cases underwent BRG1 (SMARCA4) immunohistochemical (IHC) staining, with complete loss of nuclear BRG1 expression used to identify SMARCA4-deficiency. Histopathologic evaluation and relevant clinical data were analysed. Results SMARCA4 deficiency was identified in 22 of 36 cases (61%). There were no significant differences in tumour morphology, size, association with Barrett’s, or clinical presentation between SMARCA4-deficient and SMARCA4-intact cases. However, significant differences in immunophenotype were observed, particularly regarding keratin and synaptophysin expression. Notably, eight SMARCA4-deficient cases were initially misclassified as neuroendocrine carcinoma due to synaptophysin positivity. Despite low tumour mutation burden, patients with SMARCA4-deficient UC showed improved survival when treated with immunotherapy. Additionally, three SMARCA4-deficient tumours exhibited areas of differentiated carcinoma adjacent to undifferentiated components. Conclusions Frequent synaptophysin expression in SMARCA4-deficient UC of the oesophagus can lead to diagnostic confusion with neuroendocrine carcinomas, resulting in potential mismanagement. BRG1 IHC should be incorporated in the diagnostic workup of poorly differentiated oesophageal tumours to ensure accurate classification and guide effective treatment strategies.