Integrated genomic and clinicopathologic approach distinguishes pancreatic grade 3 neuroendocrine tumor from neuroendocrine carcinoma and identifies a subset with molecular overlap Review
| Authors: | Umetsu, S. E.; Kakar, S.; Basturk, O.; Kim, G. E.; Chatterjee, D.; Wen, K. W.; Hale, G.; Shafizadeh, N.; Cho, S. J.; Whitman, J.; Gill, R. M.; Jones, K. D.; Navale, P.; Bergsland, E.; Klimstra, D.; Joseph, N. M. |
| Review Title: | Integrated genomic and clinicopathologic approach distinguishes pancreatic grade 3 neuroendocrine tumor from neuroendocrine carcinoma and identifies a subset with molecular overlap |
| Abstract: | Distinguishing grade 3 pancreatic neuroendocrine tumor (G3 PanNET) from neuroendocrine carcinoma (PanNEC) is a known diagnostic challenge, and accurate classification is critical because clinical behavior and therapies differ. Although current recommendations suggest that immunohistochemistry for p53, Rb, ATRX, and DAXX can distinguish most cases, some cases remain difficult to classify using this approach. In this study, we reviewed 47 high-grade neoplasms originally diagnosed as pancreatic neuroendocrine neoplasms. In addition to the currently recommended stains, we performed capture-based sequencing of approximately 500 cancer genes and immunohistochemistry for p16 and trypsin or chymotrypsin. Using an integrated molecular and clinicopathologic approach, 42 (89%) of 47 cases had a clear final diagnosis of either G3 PanNET (n = 17), PanNEC (n = 17), or mixed acinar-NEC (n = 8). The 17 G3 PanNETs demonstrated frequent alterations in MEN1 (71%), DAXX (47%), ATRX (24%), TSC2 (35%), SETD2 (42%), and CDKN2A (41%). Contrary to prior reports, TP53 alterations were also common in G3 PanNETs (35%) but were always mutually exclusive with CDKN2A alterations in this group. The 17 PanNECs demonstrated frequent alterations in TP53 (88%), cell cycle genes RB1 (47%), CCNE1/CCND1 (12%), CDKN2A (29%), and in KRAS (53%) and SMAD4 (41%); TP53 was coaltered with a cell cycle gene in 76% of PanNECs. Diffuse strong p16 staining was observed in 69% of PanNECs in contrast to 0% of G3 PanNETs. The 8 acinar-NECs had recurrent alterations in ATM (25%), APC (25%), and STK11 (25%). Five cases remained difficult to classify, 3 of which exhibited overlapping molecular features with alterations in MEN1 with or without ATRX, and RB1 with or without TP53, making it unclear whether to classify as PanNET or PanNEC. Our data demonstrate that molecular profiling and immunohistochemistry for p16 greatly improve the diagnostic accuracy of high-grade pancreatic neuroendocrine neoplasms and identify a subset of rare cases with overlapping features of both PanNET and PanNEC. Published by Elsevier Inc. |
| Keywords: | genetics; pancreatic neoplasms; pancreas; pathology; neuroendocrine tumor; pancreas tumor; carcinoma; genomics; neuroendocrine tumors; neuroendocrine carcinoma; carcinoma, neuroendocrine; next generation sequencing; molecular profile; humans; human |
| Journal Title: | Modern Pathology |
| Volume: | 36 |
| Issue: | 3 |
| ISSN: | 0893-3952 |
| Publisher: | Nature Research |
| Date Published: | 2023-03-01 |
| Start Page: | 100065 |
| Language: | English |
| DOI: | 10.1016/j.modpat.2022.100065 |
| PUBMED: | 36788102 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Review -- Source: Scopus |
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