High‐grade transformation of pancreatic neuroendocrine tumor associated with TP53 mutations: A diagnostic pitfall mimicking neuroendocrine carcinoma

Abstract Among pancreatic neuroendocrine neoplasms, mutations in ATRX , DAXX , and MEN1 are specific to neuroendocrine tumors (NETs), whereas TP53 and RB1 mutations are characteristic of neuroendocrine carcinomas (NECs). We report a case of pancreatic NET that underwent high‐grade transformation associated with acquisition of TP53 mutations. The primary pancreatic tumor consisted of conventional grade 2 NET with loss of alpha‐thalassemia/mental retardation, X‐linked expression and wild‐type TP53 , with a small focus exhibiting significant pleomorphism and increased mitotic activity of the neoplastic cells with two pathogenic TP53 mutations. Two years later, multiple liver metastases developed and were surgically resected. The metastatic tumors showed marked pleomorphism with increased mitotic activity (17/2 mm 2 ) and TP53 mutations identical to the small area with TP53 mutations in the primary tumor. Liver metastases with a single TP53 mutation were also noted. Notably, hormonal phenotype has changed during progression with decreased glucagon and increased insulin expression in the metastases. Our observations suggest that TP53 mutation can occur in pancreatic NETs during progression and can be associated with phenotypic transformation. Importantly, increased pleomorphism, mitotic activity, as well as TP53 mutations could be diagnostic pitfalls leading to an overdiagnosis of NEC.