Ki-67 assessment of pancreatic neuroendocrine neoplasms: Systematic review and meta-analysis of manual vs. digital pathology scoring

Abstract

Ki-67 assessment is a key step in the diagnosis of neuroendocrine neoplasms (NENs) from all anatomic locations. Several challenges exist related to quantifying the Ki-67 proliferation index due to lack of method standardization and inter-reader variability. The application of digital pathology coupled with machine learning has been shown to be highly accurate and reproducible for the evaluation of Ki-67 in NENs. We systematically reviewed all published studies on the subject of Ki-67 assessment in pancreatic NENs (PanNENs) employing digital image analysis (DIA). The most common advantages of DIA were improvement in the standardization and reliability of Ki-67 evaluation, as well as its speed and practicality, compared to the current gold standard approach of manual counts from captured images, which is cumbersome and time consuming. The main limitations were attributed to higher costs, lack of widespread availability (as of yet), operator qualification and training issues (if it is not done by pathologists), and most importantly, the drawback of image algorithms counting contaminating non-neoplastic cells and other signals like hemosiderin. However, solutions are rapidly developing for all of these challenging issues. A comparative meta-analysis for DIA versus manual counting shows very high concordance (global coefficient of concordance: 0.94, 95% CI: 0.83-0.98) between these two modalities. These findings support the widespread adoption of validated DIA methods for Ki-67 assessment in PanNENs, provided that measures are in place to ensure counting of only tumor cells either by software modifications or education of non-pathologist operators, as well as selection of standard regions of interest for analysis. NENs, being cellular and monotonous neoplasms, are naturally more amenable to Ki-67 assessment. However, lessons of this review may be applicable to other neoplasms where proliferation activity has become an integral part of theranostic evaluation including breast, brain, and hematolymphoid neoplasms.

Fig. 1. An example of the use of a digitalized system for assessing Ki-67 in pancreatic neuroendocrine neoplasms is shown here.

This is a particularly illustrative case due to the presence of a lymphocytic infiltrate at the tumor periphery, which represents a potential source of bias for Ki67 assessment with digital systems. A A pancreatic neuroendocrine tumor, G2, is shown. (Hematoxylin-eosin, 10x original magnification); B the digitalized system can count all cells present in a specific field, also on hematoxylin-eosin slides; C, D modern systems can select a specific area for the Ki-67 count: in this example, the field with lymphocytes has been excluded from the count, reducing potential important biases in tumor grading (Ki67 immunohistochemistry, 10x original magnification).