Esophageal carcinoma with SMARCA4 mutation: Unique diagnostic challenges

Abstract

Esophageal carcinoma with SMARCA4 deficiency or dysfunction is a recently recognized entity. This study describes the clinicopathologic features of four cases of esophageal carcinoma with SMARCA4 mutation, three with deep deletion and one with missense mutation. Patients include 3 males and 1 female, with an age range of 45–68 years old. Histologically, the neoplasms showed frequent mitotic activity, large nucleus and prominent nucleoli. Glandular differentiation was variable from not identifiable to approximately 20% in the biopsy material. Percentage of rhabdoid morphology was also variable from not identifiable to 20% of the biopsy material. For these cases, one case was diagnosed SMARCA4 deficient esophageal carcinoma based on the biopsy of a retroperitoneal lymph node showing loss of BRG1 by immunostain, and next generation sequencing confirmed deep deletion of SMARCA4. The other three cases had diagnosis of undifferentiated carcinoma or poorly differentiated carcinoma, and the SMARCA4 deep deletion or mutation was discovered by next generation sequencing. Molecular analysis showed TP53 mutation in all the three cases with SMARCA4 deep deletion. Two of the patients deceased 72 and 78 days after diagnosis, and the other two patients showed limited or no treatment response to chemotherapy. In conclusion, esophageal carcinoma with SMARCA4 mutation may pose significant diagnostic challenge for surgical pathologists due to its variable morphology and immunoprofile, and accurate classification of this entity requires recognition of the spectrum of morphology and utilization of BRG1 immunostain and next generating sequencing.