Assessment of cytologic differentiation in high-grade pancreatic neuroendocrine neoplasms: A multi-institutional study

Carlie S. Sigel, Vitor Werneck Krauss Silva, Michelle D. Reid, David Chhieng, Olca Basturk, Keith M. Sigel, Tanisha D. Daniel, David S. Klimstra, Laura H. Tang

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


BACKGROUND: Well-differentiated (WD) and poorly differentiated (PD) pancreatic neuroendocrine neoplasms are biologically distinct entities with different therapies and prognoses. WD neoplasms with elevated proliferation (Ki-67 > 20%) have been shown to have an overlapping histology with PD neuroendocrine carcinomas. This study compared expert cytomorphologic assessments of differentiation in pancreatic neuroendocrine neoplasms in a multi-institutional study. METHODS: Fine-needle aspiration specimens from pancreatic neuroendocrine neoplasms (grade 2 [G2] and grade 3 [G3] according to the 2017 World Health Organization classification; n = 72) were diagnosed independently by 3 cytopathologists as WD or PD (poorly differentiated large cell type [PD-L] or poorly differentiated small cell type [PD-S]) purely on the basis of cytomorphology. Their diagnoses were compared with a final classification supported by immunohistochemistry (retinoblastoma (RB), death domain- associated protein (DAXX), and α thalassemia/mental retardation syndrome X-linked (ATRX) protein expression), targeted mutation analysis (Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets), prior history of G1/G2 histology, and consensus. RESULTS: The rate of agreement on differentiation was 38% (15 WD cases and 12 PD cases) for the 70 cases included (55 WD cases [n = 19 G2, n = 31 G3, and n = 5 could not be graded] and 15 PD cases [n = 6 PD-S, n = 6 PD-L, and n = 3 PD, not otherwise specified). Two cases could not be classified by the employed methods. PD carcinomas had a higher rate of agreement (10 of 15 [67%]) than WD neoplasms (15 of 55 [27%]). Round nuclei and plasmacytoid cells were associated with agreement for WD cases, whereas apoptosis and angulated nuclei were associated with disagreement. Necrosis was associated with agreement for PD cases. CONCLUSIONS: A purely morphologic approach to the distinction between G2 and G3 pancreatic neuroendocrine neoplasms based on cytology can be challenging, with disagreement found among experienced cytopathologists. Cancer Cytopathol 2018;126:44-53.

Original languageEnglish
Pages (from-to)44-53
Number of pages10
JournalCancer cytopathology
Issue number1
StatePublished - Jan 2018


  • fine-needle aspiration (FNA)
  • neuroendocrine differentiation
  • pancreas
  • pancreas fine-needle aspiration
  • pancreatic neuroendocrine carcinoma (PanNEC)
  • pancreatic neuroendocrine tumor (PanNET)


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