Pancreatic neuroendocrine tumors G3 and pancreatic neuroendocrine carcinomas: Differences in basic biology and treatment

Abstract

In 2017 the World Health Organization revised the criteria for classification of pancreatic neuroendocrine neoplasms (pNENs) after a consensus conference at the International Agency for Research on Cancer. The major change in the new classification was to subclassify the original G3 group into well-differentiated pancreatic neuroendocrine tumors G3 (pNETs G3) and poorly differentiated pancreatic neuroendocrine carcinomas (pNECs), which have been gradually proven to be completely different in biological behavior and clinical manifestations in recent years. In 2019 this major change subsequently extended to NENs involving the entire digestive tract. The updated version of the pNENs grading system marks a growing awareness of these heterogeneous tumors. This review discusses the clinicopathological, genetic and therapeutic features of poorly differentiated pNECs and compare them to those of well-differentiated pNETs G3. For pNETs G3 and pNECs (due to their lower incidence), there are still many problems to be investigated. Previous studies under the new grading classification also need to be reinterpreted. This review summarizes the relevant literature from the perspective of the differences between pNETs G3 and pNECs in order to deepen understanding of these diseases and discuss future research directions.

Keywords: Clinical management; Gene sequencing; Histopathology; Neuroendocrine neoplasms; Pancreatic neuroendocrine carcinomas; Pancreatic neuroendocrine tumors G3.

Figure 1

Immunohistochemical staining (400 ×). A and B: Immunohistochemical positivity for chromogranin A (A) or synaptophysin (B) is considered to be a marker for neuroendocrine neoplasms. Mitotic figures rating [G3 26/10 high-power field (HPF)] is higher than the Ki67 index rating (G2, 16%); C and D: Four mitoses in one HPF is shown by black arrows (C) and related Ki67 immunohistochemical staining is shown in D; E and F: Hemtoxylin and eosin (H&E) staining of well-differentiated pancreatic neuroendocrine tumor G3 (E) and related Ki67 immunohistochemical staining (F); G and H: H&E staining of poorly differentiated pancreatic neuroendocrine carcinoma (G) and related Ki-67 immunohistochemical staining (H).

Figure 2

Immunohistochemical staining (400 ×). A: Loss of nuclear expression for ATRX in pancreatic neuroendocrine tumor G3; B and C: Aberrant expression for p53 (B) and loss of expression of Rb1 (C) in pancreatic neuroendocrine carcinoma.

Figure 3

High-throughput sequencing. A: Base C (red) mutates to G (blue) on the Men1 gene of chromosome 11 in pancreatic neuroendocrine tumor G3 (pNET G3); B: Base G (blue) mutates to A (green) on the ARTX gene of chromosome X in pNET G3; C: Base T (purple) mutates to A (green) on the Tp53 gene of chromosome 17 in pancreatic neuroendocrine carcinoma (pNEC); D: Base A (green) mutates to T (purple) on the Rb1 gene of chromosome 13 in pNEC.