BACKGROUND: Colorectal adenocarcinoma with enteroblastic differentiation (CAED) is a rare, aggressive variant that may lose typical intestinal markers and express oncofetal proteins, creating diagnostic confusion with hepatobiliary or pancreatic primaries. We report a metastatic rectal CAED with discordant initial pathology and an actionable ERBB2 (HER2) amplification.

CASE REPORT: A 57-year-old man presented with peritonitis and was found to have a perforated rectosigmoid tumor and multifocal hepatic lesions. He underwent emergent partial colectomy with end colostomy. The colorectal tumor showed a poorly differentiated adenocarcinoma, with clear-cell features, diffuse epithelial marker expression (MOC31/claudin-4), and enteroblastic markers (SALL4 and patchy glypican-3), but lacked CK20 and CDX2. A contemporaneous liver biopsy at an outside institution was interpreted as pancreaticobiliary adenocarcinoma. Because imaging showed no pancreatic mass and the pathologic profiles were discordant, both specimens underwent expert review; the liver lesion shared the same morphology and immunophenotype, supporting metastatic rectal CAED. Next-generation sequencing demonstrated ERBB2 amplification, KRAS/NRAS wild type status, microsatellite stability, and pathogenic SMAD4 and APC alterations. Systemic therapy with fluoropyrimidine/oxaliplatin and bevacizumab with consideration of anti-HER2 therapy was discussed, but the patient chose hospice and died 5 months after diagnosis.

CONCLUSIONS: CAED can masquerade as a non-colorectal primary tumor, particularly at metastatic sites. Parallel review of primary and metastatic tumors, judicious use of enteroblastic markers, and molecular profiling are key to securing the diagnosis and identifying potential therapeutic targets, such as ERBB2 amplification.

Keywords: Adenocarcinoma, Biomarkers, Tumor, Colorectal Neoplasms, Gene Amplification, Immunohistochemistry, Liver Neoplasms, next-generation sequencing