Prognostic and predictive significance of p53 and ATRX in neuroendocrine neoplasms of GIT and pancreas and their utility as an adjunct to accurate diagnosis

Abstract Purpose Neuroendocrine neoplasm of GIT and pancreas are heterogenous tumors with varying spectrum of clinicopathological characteristics. WHO 2019 classification, introduced Grade(G) 3 neuroendocrine tumor(NET) distinct from neuroendocrine carcinoma(NEC), to triage the patients for appropriate therapy. This distinction largely relies on morphology, which can be challenging at times. Genomic profiling has revealed TP53 and RB1 mutation in NECs while DAXX and ATRX in G3NET. Their role as biological markers in differentiating these entities and their significance as prognostic markers are not yet established. This study aims at analysing the diagnostic and prognostic role of p53 and ATRX in neuroendocrine neoplasms of GIT and Pancreas.Methodology: A single centre, ten year retrospective study. Tumour blocks of all G2, G3 NET and NEC were stained by immunohistochemistry for p53 and ATRX. Strong nuclear staining of > 50% of tumor cells for p53 was considered mutated. Nuclear staining of ATRX in < 5% of tumor cells was considered as ATRX loss.Results Mutated p53 was significantly associated with high grade tumors( NEC + G3NET) as compared to G2 tumors( p = 0.002). p53 mutation was frequent among NEC than G3 NET. Patients with mutated p53 had significantly lower survival irrespective of the grade(p = 0.001). There was no association of ATRX loss with grade or survival.Discussion G3NETs are genetically different from NECs. Molecular surrogates may play a role in accurately identifying these entities. Immunohistochemistry(IHC) for p53 has been used as surrogate for TP53 mutation in many tumors. Use of IHC for p53 in addition to histomorphology may facilitate accurate categorization NEC and G3 NET. Mutated p53 may also be used as an independent prognostic marker in Neuroendocrine tumors of GIT and Pancreas.