Correlation of Ki-67 indices from biopsy and resection specimens of neuroendocrine tumours

Abstract

INTRODUCTION Neuroendocrine tumours (NETs) are a heterogeneous group of tumours with a highly variable presentation and prognosis. Management decisions are complex. Ki-67 levels in tissue samples are a key indicator used to grade tumours and guide treatment. This study assessed whether the Ki-67 index and tumour grade generated from tissue samples correlated with that assessed in resection specimens. METHODS This was a retrospective cohort analysis of all patients who had both a tissue sample and a resection specimen analysed in our trust, a tertiary referral centre, during 2012 and 2013. RESULTS Data from 36 patients were reviewed. Ki-67 indices from tissue samples and resection specimens showed strong correlation (r=0.95, p<0.001). Tumour grading was the same in the tissue sample and resection specimens for 22 patients (61.1%). In four patients (11.1%), the tissue sample overestimated the grade while in ten (27.8%), the sample underestimated the grade. CONCLUSIONS In most cases, the Ki-67 index and tumour grade from the tissue sample matched that of the resection specimen. However, in nearly 40% of cases, the tissue sample grading did not match the resection tumour grading. In the majority of these, the tissue sample underestimated disease activity. A low Ki-67 index in a tissue sample should therefore be taken as provisional and should not, in isolation, persuade clinicians to choose a more conservative treatment approach if there is clinical, biochemical or radiological evidence suggestive of a more aggressive disease pathology.

Classification of pulmonary neuroendocrine tumors: new insights

“…A recent standardization of Ki-67 LI on biopsy samples and the corresponding surgical specimens of Lu-NETs have demonstrated that results were quite superimposable with minimal deviation, even among different observers, provided that precise methodology rules were a priori established and used in either type of material (30). In keeping with other comparative studies (33,125), it was important to start identifying hot spot regions in either type of material in order to obtain overlapping results when counting 2,000 cells, 2-mm 2spanning areas or the entire biopsy fragment(s) (30). In this way, it was possible to attribute to unpredictable sampling, tissue sizing, intra-tumor heterogeneous distribution of Ki-67 antigen and inter-observer discordance when Ki-67 LI were discrepant between biopsies and the corresponding resection specimens (30).…”

“…Another conundrum is the intra-tumor heterogeneous distribution of Ki-67 antigen likely due to the unpredictable occurrence of differentially regulated tumor cell subsets in tumors (115,120), but the consistent assessment of labeling indexes in hot spot regions will lead to more reproducible results (115). This biological phenomenon becomes particularly challenging on biopsy/cytology specimens in comparison with resection specimens (30,33,125) because of unpredictable sampling issues (the so-called tip-of-theiceberg effect or the part of the whole). Therefore, the reproducibility and clinical usefulness of Ki-67 LI in Lu-NETs have been seriously argued, with alleged superiority of mitotic count, which has remained the only proliferation criterion in tumor classifications over time (1,126,127), with no current diagnostic role for Ki-67 (1).…”

“…However, differences in cell lineage or the diverse application of defining criteria may cause some inconsistency to arise in the diagnostic, prognostic and predictive interpretation (8)(9)(10)(11). This bewildering situation becomes even more challenging and frustrating when dealing with metastatic NENs of unproven or uncertain origin and/or small-sized diagnostic material, where morphology alone may be a major pitfall in the management of tumor patients (5,(30)(31)(32)(33)(34)(35)(36).…”

Tumor growth rate as a metric of progression, response, and prognosis in pancreatic and intestinal neuroendocrine tumors

“…The lack of correlation between Ki-67 and TGR 0 in this analysis was surprising. However, known difficulties in assessment of the Ki-67 index (intra- and intertumoral staining heterogeneity and counting methods, for example) may, in part, account for this [24, 25]. Ki-67 was not identified as a potentially important prognostic factor for PFS from the exploratory multivariate analysis, despite the known importance of Ki-67 as a prognostic marker in NETs [26].…”

Updates of pancreatic neuroendocrine neoplasm in the 2017 World Health Organization classification

“…Good correlation between grading from cytology and resection specimens using the Ki‐67 index has been demonstrated by various studies . Yet the use of the Ki‐67 index in small specimens still has the tendency to underestimate the histological grade . The underestimation is attributed to tumour heterogeneity .…”