Longitudinal Changes in Ki-67 Indices in Small-Intestinal Neuroendocrine Tumours and Their Impact on Survival.
Daskalakis, Kosmas Tsoli, Marina Wedin, Maria Kos-Kudla, Beata Kogut, Angelika Srirajaskanthan, Raj Clement, Dominique S V M Giovos, Georgios Weickert, Martin O Kaltsas, Gregory
Daskalakis, Kosmas
Tsoli, Marina
Wedin, Maria
Kos-Kudla, Beata
Kogut, Angelika
Srirajaskanthan, Raj
Clement, Dominique S V M
Giovos, Georgios
Weickert, Martin O
Kaltsas, Gregory
Abstract
INTRODUCTION: The purpose of this study was to evaluate longitudinal changes in Ki-67 indices of SI-NETs and assess the impact of these in overall survival (OS).
METHODS: We screened 551 patients with SI-NETs diagnosed from 1993, through 2021, identified using the SI-NET databases from five European referral centres. Only patients with well-differentiated tumours and available baseline tumour samples and follow-up re-biopsies were included. For tumour grading, apart from 2017 WHO classification system, we applied a recently proposed SI-NET site-specific modified histopathological grading system with Ki-67 cut-offs of 5 and 10%. Uni- and multivariable regression analyses were used to determine whether there was a difference between OS in SI-NET patients stratified by increment of Ki-67 indices over time and/or progression to a higher grade.
RESULTS: We included 45 patients. Median Ki-67 index at SI-NET diagnosis was 2% (range: 0.5-15%). Thirty-three patients had Ki-67 indices <5% (70.2%), 6 had Ki-67: 5-10% (12.8%), and 8 had Ki-67 ≥10% (17%). Mean time to re-biopsy was 48.8 months (SD: ±162.5). At re-biopsy, the median change in Ki-67 index (absolute value; follow-up minus time of diagnosis) was 1% (range: -10 to +38%). An increase in Ki-67 occurred in 20 patients (42.6%); in 14 patients, the change in Ki-67 resulted in progression to higher tumour grade following the modified grading system. Patients with an increment in Ki-67 ≥1% had a median OS of 32.9 months versus 80.5 months in patients without (HR = 5.6, 95% CI: 1.42-22.02; p = 0.014). When applying the novel modified histopathological grading system for SI-NETs, patients with grade progression had a median OS of 32.9 months versus 53.7 months in those without (HR = 4.61, 95% CI: 1.22-13.54; p = 0.022). At multivariable analysis, grade progression was confirmed as an independent predictor for death (HR = 7.2, 95% CI: 1.58-32.82; p = 0.011).
CONCLUSIONS: Metachronous increment in Ki-67 indices and related grade progression over time following a site-specific modified histopathological grading system with Ki-67 cut-offs of 5 and 10% is observed in approximately 1/3 of SI-NETs subjected to re-biopsy and it is associated with worse survival outcomes.
MIDER Authors
Affiliations
The ARDEN NET Centre, European Neuroendocrine Tumour Society (ENETS) Centre of Excellence (CoE), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK.
Date
2024-08-27
Type
Article
Subject
Collections
Citation
Daskalakis K, Tsoli M, Wedin M, Kos-Kudla B, Kogut A, Srirajaskanthan R, Clement DSVM, Giovos G, Weickert MO, Kaltsas G. Longitudinal Changes in Ki-67 Indices in Small-Intestinal Neuroendocrine Tumours and Their Impact on Survival. Neuroendocrinology. 2025;115(5):402-410. doi: 10.1159/000541101. Epub 2024 Aug 27. PMID: 39191217; PMCID: PMC12169796.