Grading and Prognostication of Neuroendocrine Tumors of the Pancreas: A Comparison Study of Ki67 and PHH3

Abstract

Grading of pancreatic neuroendocrine tumors (pNETs) is currently based on mitotic rate and Ki67 proliferation index. Phosphohistone-H3 (PHH3) is an effective marker for mitosis that has been proposed to use in grading various NETs. It remains unclear which method more accurately predicts grade and clinical outcome. Cases of pNET were evaluated using immunohistochemical stains for Ki67 and PHH3. In addition, each case was evaluated for necrosis, lymphovascular invasion, and perineural invasion and compared with stage. R project statistical analysis was used for comparisons. Sixty-three cases were included in the study including 29 males and 34 females (M:F 0.9) with a median age of 59 years (ranging 34-84). There was not a significant discrepancy in the stratification of tumor grades for Ki67 and PHH3. PHH3 significantly predicted lymph node metastasis ( p=0.041). Necrosis correlated with overall survival ( p=0.017). The results suggest that PHH3 is an effective marker for determining mitotic activity and can be used alternative to Ki67. In addition, necrosis may be included in the reporting of pNET as it may play a prognostic role. Larger scale studies are warranted to understand the biology and behavior of these tumors.

Keywords: Ki67; PHH3; mitosis; neuroendocrine tumor; pancreas.

Figure 1.

Grade 1 pancreatic neuroendocrine tumor (A) with Ki67 with a proliferation index of <2% (B) and phosphohistone-H3 (PHH3) showing no mitotic activity (C). The H&E stain of grade 2 pancreatic neuroendocrine tumor with two mitotic figures (arrows; D) showing increased Ki67 with a proliferation index of 3–20% (E) and increased mitotic activity by PHH3 (three mitoses per high power field; F). High-grade (grade 3) tumor (G) with >20% proliferation rate via Ki67 (H) and increased mitotic figures highlighted by the PHH3 stain (I). The scale size is the same for all the figures. Scale, 90 µm.

Figure 2.

Scatter plots for phosphohistone-H3 (PHH3) (A) and Ki67 (B) stratified by the mitotic counts; within each subfigure, the x-axis is the sample index, the y-axis is PHH3/Ki67, and the highlighted is the corresponding mitotic counts (n=63).