Cancer Res Treat.  2020 Jan;52(1):263-276. 10.4143/crt.2019.192.

Pancreatic High-Grade Neuroendocrine Neoplasms in the Korean Population: A Multicenter Study

  • 1Department of Pathology, Seoul National University Hospital, Seoul, Korea
  • 2Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
  • 3Department of Pathology, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Incheon, Korea
  • 4Department of Pathology, International St. Mary's Hospital, Catholic Kwandong University College of Medicine, Incheon, Korea
  • 5Department of Pathology, Saint Maria Pathology, Busan, Korea
  • 6Department of Pathology, Chonnam National University Medical School, Gwangju, Korea
  • 7Department of Pathology, Eulji University Hospital, Daejeon, Korea
  • 8Department of Pathology, Seegene Medical Foundation, Seoul, Korea
  • 9Department of Pathology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
  • 10Department of Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
  • 11Department of Pathology, Inha University Hospital, Incheon, Korea
  • 12Department of Pathology, National Health Insurance Service Ilsan Hospital, Goyang, Korea
  • 13Department of Pathology, Soon Chun Hyang University Seoul Hospital, Seoul, Korea
  • 14Department of Pathology, Kosin University Gospel Hospital, Busan, Korea
  • 15Department of Pathology, Yonsei University Wonju College of Medicine, Wonju, Korea
  • 16Department of Pathology, Inje University Seoul Paik Hospital, Seoul, Korea
  • 17Department of Pathology, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
  • 18Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
  • 19Department of Pathology, Kyung Hee University College of Medicine, Seoul, Korea
  • 20Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea


The most recent 2017 World Health Organization (WHO) classification of pancreatic neuroendocrine neoplasms (PanNENs) has refined the three-tiered 2010 scheme by separating grade 3 pancreatic neuroendocrine tumors (G3 PanNETs) from poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs). However, differentiating between G3 Pan- NETs and PanNECs is difficult in clinical practice.
Materials and Methods
Eighty-two surgically resected PanNENs were collected from 16 institutions and reclassified according to the 2017 WHO classification based on the histological features and proliferation index (mitosis and Ki-67). Immunohistochemical stains for ATRX, DAXX, retinoblastoma, p53, Smad4, p16, and MUC1 were performed for 15 high-grade PanNENs.
Re-classification resulted in 20 G1 PanNETs (24%), 47 G2 PanNETs (57%), eight G3 well-differentiated PanNETs (10%), and seven poorly differentiated PanNECs (9%). PanNECs showed more frequent diffuse nuclear atypia, solid growth patterns and apoptosis, less frequent organoid growth and regular vascular patterns, and absence of low-grade PanNET components than PanNETs. The Ki-67 index was significantly higher in PanNEC (58.2%± 15.1%) compared to G3 PanNET (22.6%±6.1%, p < 0.001). Abnormal expression of any two of p53, p16, MUC1, and Smad4 could discriminate PanNECs from G3 PanNETs with 100% specificity and 87.5% sensitivity.
Histological features supporting the diagnosis of PanNECs over G3 PanNETs were the absence of a low-grade PanNET component in the tumor, the presence of diffuse marked nuclear atypia, solid growth pattern, frequent apoptosis and markedly increased proliferative activity with homogeneous Ki-67 labeling. Immunohistochemical stains for p53, p16, MUC1, and Smad4 may be helpful in distinguishing PanNECs from G3 PanNETs in histologically ambiguous cases, especially in diagnostic practice when only small biopsied tissues are available.


Pancreas; Neuroendocrine tumors; Neuroendocrine carcinoma; Immunohistochemistry
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