title: Interlaboratory variability of MIB1 staining in well-differentiated pancreatic neuroendocrine tumors.
abstract: Neuroendocrine tumors (NET) are routinely graded and staged to judge prognosis. Proliferation index using MIB1 staining has been introduced to assess grading. There are vivid discussions on cutoff definitions, automated counting, and interobserver variability. However, no data exist regarding interlaboratory reproducibility for low proliferation indices which are of importance to discriminate between G1 and G2 NET. We performed MIB1 staining in three different university hospital-based pathology laboratories on a tissue micro array (TMA) of a well-characterized patient cohort, containing pancreatic NET of 61 patients. To calculate the proliferation index, number of positive tumor nuclei was divided by the total number of tumor nuclei. Labeling index was compared to mitotic counts in whole tissue sections and to clinical outcome. Linear regression analysis, intraclass comparison, and log-rank analysis were performed. Intraclass correlation showed moderate-to-fair agreement. Especially low proliferating tumors were affected by interlaboratory differences. Log-rank analysis was performed for each lab and resulted in three different cutoffs (5.0, 3.0, and 0.5 %). Every calculated cutoff stratified the patient cohort to a significant extent for the underlying stain (p < 0.001, <0.001, and <0.001) but showed no or lesser significance when applied to the other stains. Significant and relevant interlab differences for MIB1 exist. Since the MIB1 proliferation index influences grading, local cutoffs or external standardization should urgently be introduced to achieve reliability and reproducibility.
authors.affiliation: University of Bern, Institute of Pathology, Murtenstr. 31, CH-3012, Bern, Switzerland. annika.blank@pathology.unibe.ch.
authors.forename: Annika
authors.initials: A
authors.lastname: Blank
authors.affiliation: Department of Cardiology, Pneumology and Internal Intensive Care Medicine, Klinikum Neuperlach, Städtisches Klinikum München GmbH, Oskar-Maria-Graf-Ring 5, 83575, Munich, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Wehweck
authors.affiliation: University of Bern, Institute of Pathology, Murtenstr. 31, CH-3012, Bern, Switzerland.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Marinoni
authors.affiliation: University of Bern, Institute of Pathology, Murtenstr. 31, CH-3012, Bern, Switzerland.
authors.forename: Laura Amanda
authors.initials: LA
authors.lastname: Boos
authors.affiliation: University of Heidelberg, Institute of Pathology, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Bergmann
authors.affiliation: University of Bern, Institute of Pathology, Murtenstr. 31, CH-3012, Bern, Switzerland.
authors.forename: Anja Maria
authors.initials: AM
authors.lastname: Schmitt
authors.affiliation: University of Bern, Institute of Pathology, Murtenstr. 31, CH-3012, Bern, Switzerland.
authors.forename: Aurel
authors.initials: A
authors.lastname: Perren
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008940:Mitotic Index / Q000379:methods; D060787:Neoplasm Grading / Q000379:methods; D018358:Neuroendocrine Tumors / Q000175:diagnosis*; D015588:Observer Variation; D010190:Pancreatic Neoplasms / Q000473:pathology*; D011379:Prognosis; D015203:Reproducibility of Results; D013194:Staining and Labeling; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor
keywords: Grading; Interlaboratory variability; Ki67; MIB1; Neuroendocrine