Detecting Somatic Mutations for Well-Differentiated Pancreatic Neuroendocrine Tumors in Endoscopic Ultrasound-Guided Fine Needle Aspiration with Next-Generation Sequencing.
Journal
Annals of surgical oncology
ISSN: 1534-4681
Titre abrégé: Ann Surg Oncol
Pays: United States
ID NLM: 9420840
Informations de publication
Date de publication:
Nov 2023
Nov 2023
Historique:
received:
03
03
2023
accepted:
03
07
2023
pubmed:
25
7
2023
medline:
25
7
2023
entrez:
24
7
2023
Statut:
ppublish
Résumé
Pancreatic neuroendocrine tumors (PanNETs) exhibit heterogenous behavior, whereby some small tumors are aggressive with a propensity for metastasis. Detection of somatic mutations associated with aggressive biology may help with patient stratification and surgical decision-making in patients with well-differentiated PanNETs. Using next-generation sequencing (NGS), we investigated the feasibility of detecting somatic mutations in endoscopic ultrasound-guided, fine-needle aspiration (EUS-FNA) specimens and determining the mutational concordance between the EUS-FNA specimens and the primary tumors. Thirty-eight patients with well-differentiated, nonfunctioning PanNETs were obtained from two tertiary referral centers. Patient demographic characteristics and tumor, clinicopathologic features were collected. Tissue from both the EUS-FNA specimen and the primary tumor was extracted from archival tissue blocks. NGS using a panel of ten genes was performed on both samples. In our series, the median age was 61.1 years. Tumors were predominantly left-sided (60.5%) and unifocal (94.7%). The median tumor size was 2.2 cm. NGS detected somatic mutations in 29% of primary tumors and 36.8% of EUS-FNA specimens. In primary tumors, DAXX/ATRX mutations were predominantly detected (63.6%). In EUS-FNA specimens, MEN1 mutations were predominantly detected (64.3%). Among non-wild-type specimens, mutational concordance was achieved in 31.6% of cases. In 11 patients with a detectable mutation in the primary tumor, a mutation was detected in the EUS-FNA specimen in 45.5% of cases, with a mutational concordance of 54.5%. NGS can detect somatic mutations in EUS-FNA specimens of well-differentiated PanNETs. Efforts to improve detection sensitivity and mutational concordance are required to overcome current technical limitations.
Sections du résumé
BACKGROUND
BACKGROUND
Pancreatic neuroendocrine tumors (PanNETs) exhibit heterogenous behavior, whereby some small tumors are aggressive with a propensity for metastasis. Detection of somatic mutations associated with aggressive biology may help with patient stratification and surgical decision-making in patients with well-differentiated PanNETs. Using next-generation sequencing (NGS), we investigated the feasibility of detecting somatic mutations in endoscopic ultrasound-guided, fine-needle aspiration (EUS-FNA) specimens and determining the mutational concordance between the EUS-FNA specimens and the primary tumors.
METHODS
METHODS
Thirty-eight patients with well-differentiated, nonfunctioning PanNETs were obtained from two tertiary referral centers. Patient demographic characteristics and tumor, clinicopathologic features were collected. Tissue from both the EUS-FNA specimen and the primary tumor was extracted from archival tissue blocks. NGS using a panel of ten genes was performed on both samples.
RESULTS
RESULTS
In our series, the median age was 61.1 years. Tumors were predominantly left-sided (60.5%) and unifocal (94.7%). The median tumor size was 2.2 cm. NGS detected somatic mutations in 29% of primary tumors and 36.8% of EUS-FNA specimens. In primary tumors, DAXX/ATRX mutations were predominantly detected (63.6%). In EUS-FNA specimens, MEN1 mutations were predominantly detected (64.3%). Among non-wild-type specimens, mutational concordance was achieved in 31.6% of cases. In 11 patients with a detectable mutation in the primary tumor, a mutation was detected in the EUS-FNA specimen in 45.5% of cases, with a mutational concordance of 54.5%.
CONCLUSIONS
CONCLUSIONS
NGS can detect somatic mutations in EUS-FNA specimens of well-differentiated PanNETs. Efforts to improve detection sensitivity and mutational concordance are required to overcome current technical limitations.
Identifiants
pubmed: 37488390
doi: 10.1245/s10434-023-13965-8
pii: 10.1245/s10434-023-13965-8
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
7720-7730Informations de copyright
© 2023. Society of Surgical Oncology.
Références
Partelli S, Bartsch DK, Capdevila J, et al. ENETS consensus guidelines for the standards of care in neuroendocrine tumours: surgery for small intestinal and pancreatic neuroendocrine tumours. Neuroendocrinology. 2017;105(3):255–65. https://doi.org/10.1159/000464292 .
doi: 10.1159/000464292
pubmed: 28237989
Lawrence B, Gustafsson BI, Chan A, Svejda B, Kidd M, Modlin IM. The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin N Am. 2011;40(1):1–18. https://doi.org/10.1016/j.ecl.2010.12.005 .
doi: 10.1016/j.ecl.2010.12.005
Sadot E, Reidy-Lagunes DL, Tang LH, et al. Observation versus resection for small asymptomatic pancreatic neuroendocrine tumors: a matched case–control study. Ann Surg Oncol. 2016;23(4):1361–70. https://doi.org/10.1245/s10434-015-4986-1 .
doi: 10.1245/s10434-015-4986-1
pubmed: 26597365
Halfdanarson TR, Rabe KG, Rubin J, Petersen GM. Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Ann Oncol. 2008;19(10):1727–33. https://doi.org/10.1093/annonc/mdn351 .
doi: 10.1093/annonc/mdn351
pubmed: 18515795
pmcid: 2735065
NCCN. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: Neuroendocrine and adrenal tumors. Available at: http://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf . Accessed 1 Dec 2022.
Howe JR, Merchant NB, Conrad C, et al. The North American Neuroendocrine Tumor Society consensus paper on the surgical management of pancreatic neuroendocrine tumors. Pancreas. 2020;49(1):1–33. https://doi.org/10.1097/MPA.0000000000001454 .
doi: 10.1097/MPA.0000000000001454
pubmed: 31856076
pmcid: 7029300
Haynes AB, Deshpande V, Ingkakul T, et al. Implications of incidentally discovered, nonfunctioning pancreatic endocrine tumors: short-term and long-term patient outcomes. Arch Surg. 2011;146(5):534–8. https://doi.org/10.1001/archsurg.2011.102 .
doi: 10.1001/archsurg.2011.102
pubmed: 21576607
pmcid: 3688044
Cherenfant J, Stocker SJ, Gage MK, et al. Predicting aggressive behavior in nonfunctioning pancreatic neuroendocrine tumors. Surgery. 2013;154(4):785–93. https://doi.org/10.1016/j.surg.2013.07.004 .
doi: 10.1016/j.surg.2013.07.004
pubmed: 24074416
Falconi M, Eriksson B, Kaltsas G, et al. ENETS consensus guidelines update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors. Neuroendocrinology. 2016;103(2):153–71. https://doi.org/10.1159/000443171 .
doi: 10.1159/000443171
pubmed: 26742109
Ito T, Igarashi H, Jensen RT. Pancreatic neuroendocrine tumors: clinical features, diagnosis and medical treatment: advances. Best Pract Res Clin Gastroenterol. 2012;26(6):737–53. https://doi.org/10.1016/j.bpg.2012.12.003 .
doi: 10.1016/j.bpg.2012.12.003
pubmed: 23582916
pmcid: 3627221
Morgan RE, Pommier SJ, Pommier RF. Expanded criteria for debulking of liver metastasis also apply to pancreatic neuroendocrine tumors. Surgery. 2018;163(1):218–25. https://doi.org/10.1016/j.surg.2017.05.030 .
doi: 10.1016/j.surg.2017.05.030
pubmed: 29103583
Ito T, Sasano H, Tanaka M, et al. Epidemiological study of gastroenteropancreatic neuroendocrine tumors in Japan. J Gastroenterol. 2010;45(2):234–43. https://doi.org/10.1007/s00535-009-0194-8 .
doi: 10.1007/s00535-009-0194-8
pubmed: 20058030
Partelli S, Gaujoux S, Boninsegna L, et al. Pattern and clinical predictors of lymph node involvement in nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs). JAMA Surg. 2013;148(10):932–9. https://doi.org/10.1001/jamasurg.2013.3376 .
doi: 10.1001/jamasurg.2013.3376
pubmed: 23986355
Bettini R, Partelli S, Boninsegna L, et al. Tumor size correlates with malignancy in nonfunctioning pancreatic endocrine tumor. Surgery. 2011;150(1):75–82. https://doi.org/10.1016/j.surg.2011.02.022 .
doi: 10.1016/j.surg.2011.02.022
pubmed: 21683859
Vagefi PA, Razo O, Deshpande V, et al. Evolving patterns in the detection and outcomes of pancreatic neuroendocrine neoplasms: the Massachusetts General Hospital experience from 1977 to 2005. Arch Surg. 2007;142(4):347–54. https://doi.org/10.1001/archsurg.142.4.347 .
doi: 10.1001/archsurg.142.4.347
pubmed: 17438169
pmcid: 3979851
Yang M, le Tian B, Zhang Y, et al. Evaluation of the World Health Organization 2010 grading system in surgical outcome and prognosis of pancreatic neuroendocrine tumors. Pancreas. 2014;43(7):1003–8. https://doi.org/10.1097/MPA.0000000000000153 .
doi: 10.1097/MPA.0000000000000153
pubmed: 24945681
Karakaş Y, Laçin Ş, Kurtulan O, et al. Prognostic value of the 2017 World Health Organization Classification System for gastric neuroendocrine tumors: a single-center experience. Turk J Gastroenterol. 2020;31(2):91–8. https://doi.org/10.5152/tjg.2020.18919 .
doi: 10.5152/tjg.2020.18919
pubmed: 32141816
pmcid: 7062132
Boutsen L, Jouret-Mourin A, Borbath I, van Maanen A, Weynand B. Accuracy of pancreatic neuroendocrine tumour grading by endoscopic ultrasound-guided fine needle aspiration: analysis of a large cohort and perspectives for improvement. Neuroendocrinology. 2018;106(2):158–66. https://doi.org/10.1159/000477213 .
doi: 10.1159/000477213
pubmed: 28494461
Fujimori N, Osoegawa T, Lee L, et al. Efficacy of endoscopic ultrasonography and endoscopic ultrasonography-guided fine-needle aspiration for the diagnosis and grading of pancreatic neuroendocrine tumors. Scand J Gastroenterol. 2016;51(2):245–52. https://doi.org/10.3109/00365521.2015.1083050 .
doi: 10.3109/00365521.2015.1083050
pubmed: 26513346
Crinò SF, Ammendola S, Meneghetti A, et al. Comparison between EUS-guided fine-needle aspiration cytology and EUS-guided fine-needle biopsy histology for the evaluation of pancreatic neuroendocrine tumors. Pancreatology. 2021;21(2):443–50. https://doi.org/10.1016/j.pan.2020.12.015 .
doi: 10.1016/j.pan.2020.12.015
pubmed: 33390343
Paiella S, Landoni L, Rota R, et al. Endoscopic ultrasound-guided fine-needle aspiration for the diagnosis and grading of pancreatic neuroendocrine tumors: a retrospective analysis of 110 cases. Endoscopy. 2020;52(11):988–94. https://doi.org/10.1055/a-1180-8614 .
doi: 10.1055/a-1180-8614
pubmed: 32498099
Abi-Raad R, Lavik JP, Barbieri AL, Zhang X, Adeniran AJ, Cai G. Grading pancreatic neuroendocrine tumors by Ki-67 index evaluated on fine-needle aspiration cell block material. Am J Clin Pathol. 2020;153(1):74–81. https://doi.org/10.1093/ajcp/aqz110 .
doi: 10.1093/ajcp/aqz110
pubmed: 31415691
Javed AA, Pulvirenti A, Razi S, et al. Grading pancreatic neuroendocrine tumors via endoscopic ultrasound-guided fine needle aspiration: a multi-institutional study. Ann Surg. 2022. https://doi.org/10.1097/sla.0000000000005390 .
doi: 10.1097/sla.0000000000005390
pubmed: 36111892
Habib JR, Zhu Y, Yin L, et al. Reliable detection of somatic mutations for pancreatic cancer in endoscopic ultrasonography-guided fine needle aspirates with next-generation sequencing: implications from a prospective cohort study. J Gastrointest Surg. 2021;25(12):3149–59. https://doi.org/10.1007/s11605-021-05078-y .
doi: 10.1007/s11605-021-05078-y
pubmed: 34244950
Kim SW, Lee JI, Kim JW, et al. BRAFV600E mutation analysis in fine-needle aspiration cytology specimens for evaluation of thyroid nodule: a large series in a BRAFV600E-prevalent population. J Clin Endocrinol Metab. 2010;95(8):3693–700. https://doi.org/10.1210/jc.2009-2795 .
doi: 10.1210/jc.2009-2795
pubmed: 20501689
Rossi ED, Pantanowitz L, Faquin WC. The role of molecular testing for the indeterminate thyroid FNA. Genes. 2019. https://doi.org/10.3390/genes10100736 .
doi: 10.3390/genes10100736
pubmed: 31614862
pmcid: 6826576
Poller DN, Glaysher S. Molecular pathology and thyroid FNA. Cytopathology. 2017;28(6):475–81. https://doi.org/10.1111/cyt.12492 .
doi: 10.1111/cyt.12492
pubmed: 29165888
Scarpa A, Chang DK, Nones K, et al. Whole-genome landscape of pancreatic neuroendocrine tumours. Nature. 2017;543(7643):65–71. https://doi.org/10.1038/nature21063 .
doi: 10.1038/nature21063
pubmed: 28199314
Singhi AD, Liu TC, Roncaioli JL, et al. Alternative lengthening of telomeres and loss of DAXX/ATRX expression predicts metastatic disease and poor survival in patients with pancreatic neuroendocrine tumors. Clin Cancer Res. 2017;23(2):600–9. https://doi.org/10.1158/1078-0432.CCR-16-1113 .
doi: 10.1158/1078-0432.CCR-16-1113
pubmed: 27407094
Park JK, Paik WH, Lee K, Ryu JK, Lee SH, Kim YT. DAXX/ATRX and MEN1 genes are strong prognostic markers in pancreatic neuroendocrine tumors. Oncotarget. 2017;8(30):49796–806. https://doi.org/10.18632/oncotarget.17964 .
doi: 10.18632/oncotarget.17964
pubmed: 28591701
pmcid: 5564808
Arakelyan J, Zohrabyan D, Philip PA. Molecular profile of pancreatic neuroendocrine neoplasms (PanNENs): opportunities for personalized therapies. Cancer. 2021;127(3):345–53. https://doi.org/10.1002/cncr.33354 .
doi: 10.1002/cncr.33354
pubmed: 33270905
Nagtegaal ID, Odze RD, Klimstra D, et al. The 2019 WHO classification of tumours of the digestive system. Histopathology. 2020;76(2):182–8. https://doi.org/10.1111/his.13975 .
doi: 10.1111/his.13975
pubmed: 31433515
Verbeke CS. Resection margins and R1 rates in pancreatic cancer: are we there yet? Histopathology. 2008;52(7):787–96. https://doi.org/10.1111/j.1365-2559.2007.02935.x .
doi: 10.1111/j.1365-2559.2007.02935.x
pubmed: 18081813
Valero V, Saunders TJ, He J, et al. Reliable detection of somatic mutations in fine needle aspirates of pancreatic cancer with next-generation sequencing: implications for surgical management. Ann Surg. 2016;263(1):153–61. https://doi.org/10.1097/SLA.0000000000001156 .
doi: 10.1097/SLA.0000000000001156
pubmed: 26020105
Yu J, Sadakari Y, Shindo K, et al. Digital next-generation sequencing identifies low-abundance mutations in pancreatic juice samples collected from the duodenum of patients with pancreatic cancer and intraductal papillary mucinous neoplasms. Gut. 2017;66(9):1677. https://doi.org/10.1136/gutjnl-2015-311166 .
doi: 10.1136/gutjnl-2015-311166
pubmed: 27432539
Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331(6021):1199–203. https://doi.org/10.1126/science.1200609 .
doi: 10.1126/science.1200609
pubmed: 21252315
pmcid: 3144496
Batukbhai BDO, De Jesus-Acosta A. The molecular and clinical landscape of pancreatic neuroendocrine tumors. Pancreas. 2019;48(1):9–21. https://doi.org/10.1097/MPA.0000000000001189 .
doi: 10.1097/MPA.0000000000001189
pubmed: 30531241
Chatani PD, Agarwal SK, Sadowski SM. Molecular signatures and their clinical utility in pancreatic neuroendocrine tumors. Front Endocrinol. 2021;11:575620. https://doi.org/10.3389/fendo.2020.575620 .
doi: 10.3389/fendo.2020.575620
Marinoni I, Kurrer AS, Vassella E, et al. Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors. Gastroenterology. 2014;146(2):453-60.e5. https://doi.org/10.1053/j.gastro.2013.10.020 .
doi: 10.1053/j.gastro.2013.10.020
pubmed: 24148618
Li D, Rock A, Kessler J, et al. Understanding the management and treatment of well-differentiated pancreatic neuroendocrine tumors: a clinician’s guide to a complex illness. JCO Oncol Pract. 2020;16(11):720–8. https://doi.org/10.1200/JCOOP.20.00010 .
doi: 10.1200/JCOOP.20.00010
pubmed: 33085933
Kulke MH, Anthony LB, Bushnell DL, et al. NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas. Pancreas. 2010;39(6):735–52. https://doi.org/10.1097/MPA.0b013e3181ebb168 .
doi: 10.1097/MPA.0b013e3181ebb168
pubmed: 20664472
pmcid: 3100728
Shah MH, Goldner WS, Halfdanarson TR, et al. NCCN guidelines insights: neuroendocrine and adrenal tumors, version 2.2018. J Natl Compr Canc Netw. 2018;16(6):693–702. https://doi.org/10.6004/jnccn.2018.0056 .
doi: 10.6004/jnccn.2018.0056
pubmed: 29891520
Assi HA, Mukherjee S, Kunz PL, et al. Surgery versus surveillance for well-differentiated, nonfunctional pancreatic neuroendocrine tumors: an 11-year analysis of the national cancer database. Oncologist. 2020;25(2):e276–83. https://doi.org/10.1634/theoncologist.2019-0466 .
doi: 10.1634/theoncologist.2019-0466
pubmed: 32043766
Partelli S, Massironi S, Zerbi A, et al. Management of asymptomatic sporadic non-functioning pancreatic neuroendocrine neoplasms no larger than 2 cm: interim analysis of prospective ASPEN trial. Br J Surg. 2022;109(12):1186–90. https://doi.org/10.1093/bjs/znac267 .
doi: 10.1093/bjs/znac267
pubmed: 35986682
pmcid: 10364756
Pea A, Yu J, Marchionni L, et al. Genetic analysis of small well-differentiated pancreatic neuroendocrine tumors identifies subgroups with differing risks of liver metastases. Ann Surg. 2020;271(3):566–73. https://doi.org/10.1097/SLA.0000000000003022 .
doi: 10.1097/SLA.0000000000003022
pubmed: 30339629
Eusebi LH, Thorburn D, Toumpanakis C, et al. Endoscopic ultrasound-guided fine-needle aspiration vs. fine-needle biopsy for the diagnosis of pancreatic neuroendocrine tumors. Endosc Int Open. 2019;7(11):E1393–2139. https://doi.org/10.1055/a-0967-4684 .
doi: 10.1055/a-0967-4684
pubmed: 31673610
pmcid: 6805236
Asokkumar R, Yung Ka C, Loh T, et al. Comparison of tissue and molecular yield between fine-needle biopsy (FNB) and fine-needle aspiration (FNA): a randomized study. Endosc Int Open. 2019;07(08):E955–63. https://doi.org/10.1055/a-0903-2565 .
doi: 10.1055/a-0903-2565
Heidsma CM, Tsilimigras DI, Rocha F, et al. Clinical relevance of performing endoscopic ultrasound-guided fine-needle biopsy for pancreatic neuroendocrine tumors less than 2 cm. J Surg Oncol. 2020;122(7):1393–400. https://doi.org/10.1002/jso.26158 .
doi: 10.1002/jso.26158
pubmed: 32783272
Mastrosimini MG, Manfrin E, Remo A, et al. Endoscopic ultrasound fine-needle biopsy to assess DAXX/ATRX expression and alternative lengthening of telomeres status in non-functional pancreatic neuroendocrine tumors. Pancreatology. 2023. https://doi.org/10.1016/j.pan.2023.05.002 .
doi: 10.1016/j.pan.2023.05.002
pubmed: 37169669