Evaluation of chromatin remodelers in pancreatic neuroendocrine neoplasms.

Abstract

652 Background: Pancreatic neuroendocrine neoplasms (PanNENs) are rare entities comprising 1-2% of gastroenteropancreatic neoplasms with an annual incidence of 0.48/100,000 population in the world. The molecular pathways underpinning the entity are less explored owing to its rarity. We aimed to analyse and correlate the expression of chromatin remodelers in PanNENs from Indian subcontinent. Methods: An ambispective study (prospective 2014-2018 as well as retrospective 2018-2021) was conducted. Haematoxylin and eosin stained slides with immunohistochemistry slides (chromogranin, synaptophysin) of 73 cases of PanNENs were retrieved from archives of Department of Pathology, AlIMS, New Delhi and evaluated for assessment of histopathological parameters. Following slide review, grading and staging were done based on WHO 2017 Classification and AJCC eighth edition respectively. Representative formalin fixed paraffin embedded block was selected after slide review and retrieved for performing immunohistochemical staining with antibodies against ATRX, DAXX, SETD2, H3K36Me3 and ARID1A using Ultra Vision Quanto polymer detection system by Thermo Fisher Scientific. Data was analysed using STATA version SE14. Results: Study cohort of 73 PanNENs had a mean age of presentation 41 years (Range: 8 years -70 years) and male to female ratio of 1.43:1. Majority of the tumors in our study were non functional (63.01%). Loss of nuclear expression of ATRX/DAXX (at least one marker) was seen in 26/73 (35.62%) cases. Loss of expression had significant correlation with pathological stage of the tumor, presence of distant metastasis and adverse prognostic outcome (p value-<0.05). Lower grade tumors with low to intermediate ki67 index had higher preponderance for loss of expression of ARID1A. Loss of expression of any of the chromatin remodelers (ATRX/DAXX/ARID1A/H3K36Me3) was noted in 44/73 cases (60.27%) and was more frequently associated with advanced stage of tumor or recurrence/metastasis/death (p value-0.005). Conclusions: Loss of chromatin remodelers such as ATRX, DAXX, ARID1A, SETD2 and H3K36ME3 is involved in the pathogenesis of pancreatic neuroendocrine neoplasms and are associated with adverse outcomes, so loss or lower immunohistochemical expression for these can serve as a poor prognostic factor and guide for adjuvant therapy.