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Prospective, Multi-Institutional, Real-Time Next-Generation Sequencing of Pancreatic Cyst Fluid Reveals Diverse Genomic Alterations that Improve the Clinical Management of Pancreatic Cysts. Gastroenterology Paniccia, A., Polanco, P. M., Boone, B. A., Wald, A. I., McGrath, K., Brand, R. E., Khalid, A., Kubiliun, N., O'Broin-Lennon, A. M., Park, W. G., Klapman, J., Tharian, B., Inamdar, S., Fasanella, K., Nasr, J., Chennat, J., Das, R., DeWitt, J., Easler, J. J., Bick, B., Singh, H., Fairley, K. J., Sarkaria, S., Sawas, T., Skef, W., Slivka, A., Tavakkoli, A., Thakkar, S., Kim, V., Vanderveldt, H. D., Richardson, A., Wallace, M. B., Brahmbhatt, B., Engels, M., Gabbert, C., Dugum, M., El-Dika, S., Bhat, Y., Ramrakhiani, S., Bakis, G., Rolshud, D., Millspaugh, G., Tielleman, T., Schmidt, C., Mansour, J., Marsh, W., Ongchin, M., Centeno, B., Monaco, S. E., Ohori, N. P., Lajara, S., Thompson, E. D., Hruban, R. H., Bell, P. D., Smith, K., Permuth, J. B., Vandenbussche, C., Ernst, W., Grupillo, M., Kaya, C., Hogg, M., He, J., Wolfgang, C. L., Lee, K. K., Zeh, H., Zureikat, A., Nikiforova, M. N., Singhi, A. D. 2022

Abstract

BACKGROUND AND AIMS: Next-generation sequencing (NGS) of pancreatic cyst fluid is a useful adjunct in the assessment of pancreatic cyst (PC) patients. However, previous studies have been retrospective or single institutional experiences. The aim of this study was to prospectively evaluate NGS on a multi-institutional cohort of PC patients in real-time.METHODS: The performance of a 22-gene NGS panel (PancreaSeq) was first retrospectively confirmed and then within a two-year timeframe, PancreaSeq testing was prospectively used to evaluate endoscopic ultrasound (EUS)-guided fine-needle aspiration PC fluid from 31 institutions. PancreaSeq results were correlated with EUS findings, ancillary studies, current pancreatic cyst guidelines, follow-up, and expanded testing (Oncomine) of postoperative specimens.RESULTS: Among 1933 PCs prospectively tested, 1887 (98%) specimens from 1832 patients were satisfactory for PancreaSeq testing. Follow-up was available for 1216 (66%) patients (median, 23 months). Based on 251 (21%) patients with surgical pathology, MAPK/GNAS mutations had 90% sensitivity and 100% specificity for a mucinous cyst (PPV, 100%; NPV, 77%). Upon exclusion of low-level variants, the combination of MAPK/GNAS and TP53/SMAD4/CTNNB1/mTOR alterations had 88% sensitivity and 98% specificity for advanced neoplasia (PPV, 97%; NPV, 93%). Inclusion of cytopathologic evaluation to PancreaSeq testing improved the sensitivity to 93% and maintained a high specificity of 95% (PPV, 92%); NPV, 95%). In comparison, other modalities and current pancreatic cyst guidelines, such as the AGA and IAP/Fukuoka guidelines, show inferior diagnostic performance. The sensitivities and specificities of VHL and MEN1/LOH alterations were 71% and 100% for serous cystadenomas (SCAs) (PPV, 100%; NPV, 98%), and 68% and 98% for pancreatic neuroendocrine tumors (PanNETs) (PPV, 85%; NPV, 95%), respectively. Upon follow-up, SCAs with TP53/TERT mutations exhibited interval growth, while PanNETs with LOH of =3 genes tended to have distant metastasis. None of the 965 patients who did not undergo surgery developed malignancy. Postoperative Oncomine testing identified mucinous cysts with BRAF fusions and ERBB2 amplification, and advanced neoplasia with CDKN2A alterations.CONCLUSIONS: PancreaSeq was not only sensitive and specific for various PC types and advanced neoplasia arising from mucinous cysts, but also reveals the diversity of genomic alterations seen in PCs and their clinical significance.

View details for DOI 10.1053/j.gastro.2022.09.028

View details for PubMedID 36209796