Ki-67 Index and Somatostatin Receptor Expression as Prognostic Markers in Patients with Pancreatic Neuroendocrine Tumours: A Review

Abstract

The Ki-67 proliferation index is the marker on which pancreatic neuroendocrine tumours are graded, and somatostatin receptor expression is the marker on which they are imaged and treated. They are usually discussed as a pair. In the one cohort that compared them directly, the receptor outperformed the proliferation index as a predictor of survival. Objectives: To review the published evidence on Ki-67 and somatostatin receptor expression as prognostic markers in pancreatic neuroendocrine tumours: what each predicts, how reproducibly each is measured, how they relate to one another, and how immunohistochemistry compares with receptor imaging.
Material and Methods: Narrative review of resection cohorts, immunohistochemical series, imaging correlation studies and pooled analyses indexed in PubMed and the major oncology, pathology and nuclear medicine journals. Studies were eligible if they reported outcomes stratified by Ki-67 index or somatostatin receptor expression, the reproducibility of either measurement, or correlation between immunohistochemistry and receptor imaging. No new patient data were generated; every estimate quoted is one published by the original investigators. Results: In 99 resected tumours, SSTR-2a was expressed in 80.1 per cent and SSTR-5 in 24.2 per cent. SSTR-2a positivity was associated with improved overall survival, with cumulative rates of 97.5, 91.5 and 82.9 per cent at one, three and five years, and on multivariable analysis it was the stronger predictor, with a hazard ratio of 0.2 (95% CI 0.1-0.8) against 0.8 (95% CI 0.1-5.7) for high Ki-67. SSTR-5 was not associated with survival. In a separate series of 279 patients, SSTR2 immunohistochemistry was an independent prognostic marker for overall survival (HR 0.82, 95% CI 0.67-0.99), correlated with tumour uptake on receptor imaging, but was outperformed by the imaging itself, which carried a positive predictive value advantage of 27 percentage points. Ki-67 measurement remains discrepant between observers precisely at the grade boundaries of 3 and 20 per cent. Conclusion: Ki-67 is indispensable for grading but is measured least reliably at the thresholds that determine grade, and its prognostic weight in resected
disease is smaller than the emphasis placed on it suggests. Somatostatin receptor status carries independent prognostic information and, where receptor imaging is available, the imaging is the more accurate of the two receptor measurements. Abbreviations: PanNET – Pancreatic Neuroendocrine Tumour, PanNEN – Pancreatic Neuroendocrine Neoplasm, NEC – Neuroendocrine Carcinoma,
SSTR – Somatostatin Receptor, IHC – Immunohistochemistry, DIA – Digital Image Analysis, WHO – World Health Organization, ENETS – European Neuroendocrine Tumour Society, PET – Positron Emission Tomography, PRRT – Peptide Receptor Radionuclide Therapy, SSA – Somatostatin Analogue, HR – Hazard Ratio, OS – Overall Survival, HPF – High-Power Field.