Ki-67 prognostic and therapeutic decision driven marker for pancreatic neuroendocrine neoplasms (PNENs): A systematic review

Abstract

Background

We systematically evaluate the current evidence regarding Ki-67 as a prognostic factor in pancreatic neuroendocrine neoplasms to evaluate the differences of this marker in primary tumors and in distant metastases as well as the values of Ki-67 obtained by fine needle aspiration and by histology.

Methods

The literature search was carried out using the MEDLINE/PubMed database, and only papers published in the last 10 years were selected.

Results

The pancreatic tissue suitable for Ki-67 evaluation was obtained from surgical specimens in the majority of the studies. There was a concordance of 83% between preoperative and postoperative Ki-67 evaluation. Pooling the data of the studies which compared the Ki-67 values obtained in both cytological and surgical specimens, we found that they were not related. The assessment of Ki-67 was manual in the majority of the papers considered for this review. In order to eliminate manual counting, several imaging methods have been developed but none of them are routinely used at present. Twenty-two studies also explored the role of Ki-67 utilized as a prognostic marker for pancreatic neuroendocrine neoplasms and the majority of them showed that Ki-67 is a good prognostic marker of disease progression. Three studies explored the Ki-67 value in metastatic sites and one study demonstrated that, in metachronous and synchronous liver metastases, there was no significant variation in the index of proliferation.

Conclusions

Ki-67 is a reliable prognostic marker for pancreatic neuroendocrine neoplasms.

Introduction

The main adverse prognostic factors of neuroendocrine neoplasms (NENs) are the localization of the primary tumor (i.e. pancreatic NENs generally have a worse prognosis than intestinal NENs), the stage according to the tumor-node-metastasis (TNM) classification [1], and the histopathology according to the World Health Organization (WHO) classification, which expresses both the morphological appearance of the tumor and its proliferative activity (number of mitoses and proliferation index represented by Ki-67) [2].

In brief, The World Health Oraganization (WHO) 2010 classification distinguishes between well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs) of small or large cell type. NETs are then divided according to a grading scheme based on mitotic count or Ki 67 index in NETs-G1 (with a mitotic count <2 per 10 high-power fields (HPF) and/or ≤2% Ki67 index), and NETs-G2 (with a mitotic count 2–20 per 10 HPF and/or 3–20% Ki67 index). All NECs are graded G3 (with a mitotic count >20 per 10 HPF and/or >20% Ki67 index) [2]. This classification has been also included in the guidelines of the European Neuroendocrine Tumor Society (ENETS) [3].

Ki-67 is an immunohistochemical stain and cells in G0 remain negative whereas cells in all other phases of the cell cycle stain positive since Ki-67 is a is a nucleolar antigen and diffuses all over the nuclear matrix only in G2 phase present only in the nuclei of cycling cells [4]. MIB-1 monoclonal antibody is the only antibody recommended by both ENETS and WHO and it is directed against different epitopes of the same proliferation-related antigen and may be used on fixed sections [5] to determine the Ki-67 labeling index which is a percentage of stained MIB-1 cells present in 500–2000 cells. This latter parameter distinguishes three different categories of grading patients, and it is now considered one of the strongest prognostic factors for NENs [6]. However, the best method to calculate the Ki67-labeling index remains controversial, as does the relative value of counting mitoses versus Ki67 labeling in determining the proliferative index [7], [8]. Finally, comparison between the different studies should be carried out with caution because the immunohistochemistry method differs at different centers, and there is probably some inter-observer variability in determining the percentage of Ki-67-positive cells [4].

Our aims were to systematically review the current evidence regarding Ki-67 as a prognostic factor in pancreatic NENs (PNENs), to evaluate the differences of this marker in primary tumors and in distant metastases as well as the values of Ki-67 obtained by fine needle aspiration and by histology.