Modified Histopathological Grading Optimizes Prediction of Survival Outcomes in Small Intestinal Neuroendocrine Tumours

Kosmas Daskalakis; Marina Tsoli; Göran Wallin; Angelika Kogut; Raj Srirajaskanthan; Christopher Harlow; Georgios Giovos; Martin O Weickert; Beata Kos-Kudla; Gregory Kaltsas

doi:10.1210/clinem/dgae111

Modified Histopathological Grading Optimizes Prediction of Survival Outcomes in Small Intestinal Neuroendocrine Tumours

J Clin Endocrinol Metab. 2024 Feb 28:dgae111. doi: 10.1210/clinem/dgae111. Online ahead of print.

Authors

Affiliations

¹ Department of Surgery, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
² 2nd Department of Surgery, "Korgialenio-Benakio", Red Cross General Hospital, 11526 Athens, Greece.
³ Endocrine Oncology Unit, 1st Department of Propaedeutic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece.
⁴ Department of Endocrinology and Neuroendocrine Neoplasms, Department of Endocrinology and Pathophysiology, Medical University of Silesia, Katowice, Poland.
⁵ ENETS Centre of Excellence, Neuroendocrine Tumour Unit, King's College Hospital, London, SE5 9RS, UK.
⁶ Department of Gastroenterology, King's College Hospital, London, SE5 9RS, UK.
⁷ The ARDEN NET Centre, European Neuroendocrine Tumour Society (ENETS) Centre of Excellence (CoE), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK.

PMID: 38415861
DOI: 10.1210/clinem/dgae111

Abstract

Context: One of the major prognostic indices in neuroendocrine tumours (NETs) is Ki67 proliferation index.

Objective: To identify optimal grading Ki-67 cut-offs to delineate differences in prognosis of patients with small intestinal NETs (SI-NETs).

Design, setting, participants: Multicentre retrospective cohort analysis of 551 SI-NET patients diagnosed from 1993 through 2021 at five European referral centres with a mean(±SD) follow-up time of 51.5(±52.9) months.

Main outcome measures: Overall- and event-free survival (OS and EFS) rates.

Results: Median age at baseline was 62.3(range:17-90) years; 252(45.7%) patients were female. All SI-NETs were well-differentiated with 326 being grade 1(G1; 59.2%), 169G2(30.7%), and only 8G3(1.5), while 48 tumours were of unspecified grade (8.7%). The median Ki67 was 2%(range:1-70%). Two-hundred forty-seven patients (44.8%) had distant metastases at baseline (stage IV), 217 locoregional disease (41.1%; stage III), whereas 29(7.1%) and 25(4.5%) presented at stages II and I, respectively. The median OS was 214.7(95%CI:152.7-276.6) months and the median EFS was 79.8(95%CI:68.2-91.5) months, respectively. In multivariable Cox-regression OS analysis, the proposed modified histopathological Ki67 grading system (K67:5-10% group: HR=2.2, 95%CI:1.15-4.31; p=0.018 and K67≥10% group: HR=5.11, 95%CI:2.87-9.09; p<0.001), age (HR=1.07, 95%CI:1.04-1.09; p<0.001), Charlson Comorbidity Index (HR=1.08, 95%CI:1-1.16; p=0.028) and TNM stage (HR=1.79, 95%CI:1.05-3.06; p=0.034) were independent predictors for death. Pertinent EFS analysis, confirmed the proposed modified histopathological Ki67 grading system (K67≥10% group: HR=4.01, 95%CI:2.6-6.37; p<0.001) and age (HR=1.04, 95%CI:1.02-1.05; p<0.001) as independent predictors for recurrence, progression and/or death.

Conclusions: Ki-67 proliferation index was a strong and independent predictor of OS and EFS. A modified histopathological grading system applying Ki-67 cut-offs of 5 and 10% could be superior to predict differences in SI-NET patient survival outcomes.

Keywords: Histopathological Grading; Small Intestinal Neuroendocrine Tumours.