Endocrine Abstracts

Background: Grade 3 pancreatic neuroendocrine tumor (G3-PanNET) and neuroendocrine carcinoma (PanNEC) are both defined by Ki67>20% and/or mitoses >20 per 2mm2. PanNET and PanNEC are thought to be molecularly distinct entities and progression from PanNET to PanNEC is considered rare. MEN1, ATRX, DAXX, and TSC1/2 mutations are common in PanNET, while TP53, RB1, KRAS, and SMAD4 mutations are typical of PanNEC. Immunostains for ATRX/DAXX/p53/Rb aid in the classification of G3-NET v NEC, and history of prior or concurrent G1/G2-NET is thought to support a G3-NET diagnosis. We have observed multiple G3 neuroendocrine neoplasms (NENs) with alterations in both NET and NEC genes, raising questions about how these cases should be classified and managed.

Methods: Next generation sequencing was performed on 31 pancreatic G3-NENs that were classified as G3-NET during routine pathology review at UCSF. An additional 20 cases of ambiguous pancreatic G3-NEN were also sequenced. Of the ambiguous cases, 10 had alterations in NET genes and were included yielding a total of 41 cases that were either diagnosed as G3-NET or were ambiguous but harbored NET alterations. Several matched prior G1/G2-NETs (n=5) were also sequenced.

Results: Of the 41 cases, 23 (56%) had history of a prior G1/G2-NET and received prior therapies, whereas the other 44% were G3 at diagnosis and treatment naive. 88% (36/41) had alterations in NET genes including in MEN1 (63%), DAXX/ATRX (37%), and TSC1/2 (31%). 27% (11/41) had alterations in both NET genes and TP53; 3 of these 11 (3/41 overall; 7.3%) had co-alteration of TP53 and RB1. Of the 11 cases with alterations in TP53 +/- RB1, 8 (73%) had prior G1/G2-NET (5 of which were also sequenced). All G1/G2 priors demonstrated shared identical mutations with the matched G3 NET in at least one NET gene, but none had alterations in TP53 or RB1.

Conclusion: Our study demonstrates that 20% of G3-PanNET harbor alterations in TP53 and another 7.3% harbor co- alteration of TP53 and RB1. Our data suggest that TP53 and RB1 alterations emerge during grade progression to G3-NET, most often (73%) in the setting of previously treated G1/G2-NET. These data raise many questions: 1) Should G3-NET with TP53 and/or RB1 alterations be classified and treated as NEC? 2) Do specific prior therapies increase the risk of acquiring TP53 and/or RB1 alterations? 3) Are outcomes worse in G3-NET with or without TP53 and/or RB1 alterations? Further studies are needed to answer these important questions.

Abstract ID 23800