The assessment of Ki-67 as a prognostic marker in neuroendocrine tumours: a systematic review and meta-analysis

Richards-Taylor, Sebastian; Ewings, Sean; Jaynes, Eleanor; Tilley, Charles; Ellis, Sarah; Armstrong, Thomas; Pearce, Neil; Cave, Judith

doi:10.1136/jclinpath-2015-203340

Cited by 49 publications

(44 citation statements)

References 29 publications

(25 reference statements)

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“…Our limits using Ki-67-Average were approximately 20% and our limits using Ki-67-Hotspot evaluation were approximately 25%. Nevertheless, our cut-off values were similar to previously established values for GEP-NEN grading [10, 39–43]. …”

Section: Discussionsupporting

confidence: 86%

Comparative evaluation of three proliferation markers, Ki-67, TOP2A, and RacGAP1, in bronchopulmonary neuroendocrine neoplasms: Issues and prospects

Neubauer

Wirtz²,

Kaemmerer

et al. 2016

Oncotarget

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The classification of bronchopulmonary neuroendocrine neoplasms (BP-NEN) into four tumor entities (typical carcinoids (TC), atypical carcinoids (AC), small cell lung cancers (SCLC), large cell neuroendocrine lung carcinomas (LCNEC)) is difficult to perform accurately, but important for prognostic statements and therapeutic management decisions. In this regard, we compared the expression of three proliferation markers, Ki-67, Topoisomerase II alpha (TOP2A), and RacGAP1, in a series of tumor samples from 104 BP-NEN patients (24 TC, 21 AC, 52 SCLC, 7 LCNEC) using different evaluation methods (immunohistochemistry (IHC): Average evaluation, Hotspot evaluation, digital image analysis; RT-qPCR).The results indicated that all three markers had increased protein and mRNA expression with poorer differentiation and correlated well with each other, as well as with grading, staging, and poor survival. Compared with Ki-67 and TOP2A, RacGAP1 allowed for a clearer prognostic statement. The cut-off limits obtained for Ki-67-Average (IHC) were TC-AC 1.5, AC-SCLC 19, and AC-LCNEC 23.5. The Hotspot evaluation generated equal to higher, the digital image analysis generally lower between-entity cut-off limits.All three markers enabled a clear-cut differentiation between the BP-NEN entities, and all methods evaluated were suitable for marker assessment. However, to define optimal cut-off limits, the Ki-67 evaluation methods should be standardized. RacGAP1 appeared to be a new marker with great potential.

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Section: Discussionsupporting

confidence: 86%

Comparative evaluation of three proliferation markers, Ki-67, TOP2A, and RacGAP1, in bronchopulmonary neuroendocrine neoplasms: Issues and prospects

Neubauer

Wirtz²,

Kaemmerer

et al. 2016

Oncotarget

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“…Such modification resulted previously in statistically significant differences in survival between G1 and G2 cases in multivariate analyses adjusted for stage, in contrary to original 2(3)% cut-off [47,48]. This result was confirmed by meta-analysis [49], which showed better ability of 5% value for prognostication in NET.…”

Section: Ki67 LI Is Imperfect Predictor Of Regional Lymph Node Metastmentioning

confidence: 88%

“…Secondly, Ki67 LI is a prognostic factor in NEN (as reviewed in [49,66]). Ki67 LI is a risk factor of progression in advanced pancreatic NEN [67].…”

Section: Significance Of Ki67 LI In Pancreatic Nenmentioning

confidence: 99%

Tissue heterogeneity contributes to suboptimal precision of WHO 2010 scoring criteria for Ki67 labeling index in a subset of neuroendocrine neoplasms of the pancreascriteria for Ki67 labeling index in a subset of neuroendocrine neoplasms of the pancreas

Liszka¹

2016

pjp

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Reporting of Ki67 labeling index (LI) is a routine in diagnostics of neuroendocrine neoplasms of the pancreas. The aim of the study was to examine whether heterogeneity of Ki67 LI distribution in primary tumoral tissue influences precision of reporting of Ki67 LI and Ki67-LI-based grade, both established in adherence to WHO 2010 guidelines. Seventy-one samples of neuroendocrine tumours (NET) and 6 samples of neuroendocrine carcinomas (NEC) of the pancreas were taken for manual counting of Ki67 LI in 25 portions of 100 cells (2500 cells in total) in 3 hot spots an in a single area of lower proliferation rate (cold spot) in each case. Both NET and NEC showed Ki67 LI heterogeneity within primary tumour. Almost 20% of NET showed higher grade when 500 cells rather than 2000 cells were counted in hot spot area. Suboptimal choice of hot spot resulted in under-grading of approximately 20% of NET. Cold spots were constantly present in NET. Heterogeneity of Ki67 LI was also present in NEC, but it virtually never resulted in under-grading. Concept and methodology of Ki67 LI counting in neuroendocrine neoplasms of the pancreas requires clarification. Efforts aiming to improve precision of assessment of Ki67 LI are needed.

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“…Current WHO and ENETS classifications rely on the Ki-67 index or mitotic count for GEP-NET grade. 23 Although SEER did not provide data on Ki-67 index or mitotic counts, we used information on differentiation grade to show that LNR retained prognostic significance after controlling for this factor. Additionally, there was considerable variability in the number of lymph nodes resected for each patient.…”

Section: Discussionmentioning

confidence: 99%

Lymph Node Metastasis in the Prognosis of Gastroenteropancreatic Neuroendocrine Tumors

Martin

Warner²,

Aronson³

et al. 2017

Pancreas

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Objectives This study aimed to determine the prognostic utility of the extent of lymph node involvement in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) by analyzing population-based data. Methods Patients in the Surveillance, Epidemiology, and End Results (SEER) registry were identified with histologically confirmed, surgically resected GEP-NETs. We divided patients into three lymph node ratio (LNR) groups based on the ratio of positive lymph nodes to total lymph nodes examined: ≤0.2, >0.2–0.5, and >0.5. Disease-specific survival was compared according to LNR group. Results We identified 3,133 patients with surgically resected GEP-NETs. Primary sites included stomach (11% of the total), pancreas (30%), colon (32%), appendix (20%), and rectum (7%). Survival was worse in patients with LNRs of ≤0.2 (hazard ratio [HR], 1.5; 95% confidence interval [CI], 1.2–2.0), >0.2–0.5 (HR, 2.0; 95% CI, 1.6–2.5), and >0.5 (HR, 3.1; 95% CI, 2.5–3.9) compared to N0 patients. Ten-year disease-specific survival decreased as LNR increased from N0 (81%) to ≤0.2 (69%), >0.2–0.5 (55%), and >0.5 (50%). Results were consistent for patients with both low and high grade tumors from most primary sites. Conclusions Degree of lymph node involvement is a prognostic factor at the most common GEP-NET sites. Higher LNR is associated with decreased survival.

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The assessment of Ki-67 as a prognostic marker in neuroendocrine tumours: a systematic review and meta-analysis

Abstract: Standardisation of grade boundaries has allowed us to combine data from multiple studies and amass a body of evidence linking Ki-67 and survival.

Cited by 49 publications

References 29 publications

Comparative evaluation of three proliferation markers, Ki-67, TOP2A, and RacGAP1, in bronchopulmonary neuroendocrine neoplasms: Issues and prospects

Comparative evaluation of three proliferation markers, Ki-67, TOP2A, and RacGAP1, in bronchopulmonary neuroendocrine neoplasms: Issues and prospects

Tissue heterogeneity contributes to suboptimal precision of WHO 2010 scoring criteria for Ki67 labeling index in a subset of neuroendocrine neoplasms of the pancreascriteria for Ki67 labeling index in a subset of neuroendocrine neoplasms of the pancreas

Lymph Node Metastasis in the Prognosis of Gastroenteropancreatic Neuroendocrine Tumors

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