Grading of Neuroendocrine Tumors With Ki-67 Requires High-quality Assessment Practices

Abstract

Gastrointestinal and pancreatic neuroendocrine tumors (NETs) arise from disseminated neuroendocrine cells, expressing general and specific neuroendocrine markers. The World Health Organization 2010 classification of NETs is based on grading them according to the proliferation index (PI), which is determined by immunohistochemical staining of the nuclear antigen Ki-67. The classification introduces Ki-67 as the most important criterion for tumor grading, influencing patients' prognoses and the choice of treatment. The aim of this study was to evaluate the assessment of PI value in NETs and its influence on tumor grading. The tumor material consisted of 51 NETs from the pancreas (n=31) and ileum (n=20). The slides were stained with the Ki-67 antibody and visualized using a polymer kit. PI was assessed visually by microscope oculars and using a public domain image analysis software, ImmunoRatio. The PI was measured from the most proliferative areas of the tumor. The PI values and tumor grade by ImmunoRatio were highly reproducible as compared with conventional assessment, which suffered from variation especially if ascertained by different observers. Computer-aided assessments had almost perfect correlation (r=0.985, r=0.987, and r=0.995) (P=0.000) and reproducibility (κ=0.886, κ=0.886, and κ=1.000) (P=0.000) in PI values and tumor grades, respectively. The PI values and tumor grade between conventional and ImmunoRatio assessments by a qualified observer were in good agreement. ImmunoRatio is a qualified diagnostic aid to more objectively analyze Ki-67 PI-based tumor grade in NETs.

Reliability of Proliferation Assessment by Ki-67 Expression in Neuroendocrine Neoplasms: Eyeballing or Image Analysis?

“…Similar findings were reported in two large studies on breast carcinoma [11,19] and in two smaller studies of neuroendocrine tumors [9,20]. However, correlation was poor (ICC = 0.13) in another study that compared 18 pathologists who evaluated 27 cases (45 images) [21].…”

The ENETS/WHO Grading System for Neuroendocrine Neoplasms of the Gastroenteropancreatic System: A Review of the Current State, Limitations and Proposals for Modifications

“…Furthermore, the actual counting time taken by the machine is about 5 min per slide – not a huge improvement over manual counting of printed photos [61]. Partially automated systems have comparable reproducibility but are more accessible (there are many free image analysis softwares available); however, they also rely on an experienced observer to select the best area for counting and assess the precision of the final count, excluding any nontumoral cells that the software may have included [63]. Therefore, for now, it seems that the method that best allies accuracy, practicality and reproducibility is manual counting from a printed image.…”

Neuroendocrine tumors of the digestive system: pathologic and molecular characteristics

“…табл. 2) [38][39][40]. Определение пролиферативной активности опу-холевых клеток с помощью подсчета индекса Ki-67 является необходимым условием современной морфо-логической диагностики и служит базой для даль-нейшей клинической оценки агрессивности течения заболевания и обоснованного назначения соответст-вующих режимов лекарственного лечения.…”