Prognostic and predictive significance of p53 and ATRX in neuroendocrine neoplasms of GIT and pancreas and their utility as an adjunct to accurate diagnosis-An eight-year retrospective study.

Introduction: Neuroendocrine neoplasms of gastrointestinal tract (GIT) and pancreas are heterogenous tumors. World Health Organization (WHO) 2019 classification introduced Grade (G)3 neuroendocrine tumor (NET) distinct from neuroendocrine carcinoma (NEC), based on molecular differences and 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 mutations in NECs, while death domain-associated protein 6 (DAXX) and alpha-thalassemia/mental retardation X-linked (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 analyzing the diagnostic and prognostic role of p53 and ATRX in neuroendocrine neoplasms of GIT and pancreas.

Methodology: A single-centre, eight-year retrospective study of neuroendocrine neoplasm of GIT and pancreas comprised G2NET, G3NET and NEC. Tumor slides 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 ATRX loss. Expression of p53 and ATRX was analyzed and correlated with tumor grades and patient survival.

Results: Fifty-five patients with gastro-entero-pancreatic neuroendocrine neoplasm were studied, comprising G2NET (58%), G3NET (16%) and NEC (26%). Median age of diagnosis was 59 years with male predominance. The pancreas was the most common site followed by the small bowel. NEC showed lower survival compared to G3 and G2NET. Mutated p53 immunohistochemical expression was more frequent among NEC than G3NET. 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.

Conclusion: G3NETs are genetically different from NECs. Use of immunohistochemistry for p53 in addition to histomorphology may facilitate accurate categorization of NEC and G3NET. Mutated p53 may also be used as an independent prognostic marker in neuroendocrine tumors of GIT and pancreas.