title: The Impact of Phosphohistone-H3-Assisted Mitotic Count and Ki67 Score in the Determination of Tumor Grade and Prediction of Distant Metastasis in Well-Differentiated Pancreatic Neuroendocrine Tumors.
abstract: This study investigated the impact of phosphohistone-H3 (PHH3)-assisted mitotic count by comparing its performance with conventional mitotic count and Ki67 score as well as the status of distant metastasis. A total of 43 surgically resected pancreatic neuroendocrine tumors (panNET) with complete follow-up information has been subjected to a standardized assessment with respect to mitotic count (both conventional and PHH3-assisted) and Ki67 score. Five participants assessed mitotic count and the time spent was recorded in both methods. All tumors were assigned to a G1 category of mitotic rate on conventional mitotic count that failed to identify three tumors with a G2 category of mitotic rate on PHH3. Near-perfect and fair agreements were achieved among observers when using PHH3 and conventional method, respectively. The mean time spent to determine mitotic count on PHH3-stained slides was significantly shorter (p < 0.001). The performance of PHH3-assisted mitotic grade category was significant as the three cases with a G2 mitotic category were associated with distant metastasis (p = 0.01). Despite its performance, the PHH3-assisted mitotic count downgraded 17 cases that were classified as G2 based on Ki67 scores in this series. The Ki67 grade category was either the same or higher than the mitotic grade category. Ten patients developed distant metastasis. Eleven tumors exhibited vascular invasion characterized by intravascular tumor cells admixed with thrombus. Our results indicate that PHH3-assisted mitotic count facilitates an accurate mitotic count with a perfect agreement among observers. The small size of this cohort is an important limitation of the current study, a G2 mitotic grade category based on PHH3 immunohistochemistry was one of the correlates of panNETs with distant metastasis. While the prognostic impact of PHH3-assisted mitotic count needs to be clarified in larger cohorts, Ki67 scores designated higher grade category in all cases; thus, it was the best determinant of the tumor grade. More importantly, the presence of vascular invasion along with the Ki67 grade category was found to be independent predictors of distant metastasis.
authors.affiliation: Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. suleozturksari@gmail.com.
authors.forename: Sule
authors.initials: S
authors.lastname: Ozturk Sari
authors.affiliation: Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Orhun Cig
authors.initials: OC
authors.lastname: Taskin
authors.affiliation: Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Gokcen
authors.initials: G
authors.lastname: Gundogdu
authors.affiliation: Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Gulcin
authors.initials: G
authors.lastname: Yegen
authors.affiliation: Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Semen
authors.initials: S
authors.lastname: Onder
authors.affiliation: Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Metin
authors.initials: M
authors.lastname: Keskin
authors.affiliation: Department of Medical Oncology, University of Bilim, Istanbul, Turkey.
authors.forename: Sezer
authors.initials: S
authors.lastname: Saglam
authors.affiliation: Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Ozluk
authors.affiliation: Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Mine
authors.initials: M
authors.lastname: Gulluoglu
authors.affiliation: Department of Pathology, University Health Network, Toronto, ON, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
authors.forename: Ozgur
authors.initials: O
authors.lastname: Mete
mesh_terms: D000328:Adult; D000368:Aged; D018572:Disease-Free Survival; D005260:Female; D006657:Histones / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D008875:Middle Aged; D008940:Mitotic Index / Q000379:methods*; D060787:Neoplasm Grading / Q000379:methods*; D009362:Neoplasm Metastasis / Q000473:pathology; D018358:Neuroendocrine Tumors / Q000401:mortality / Q000473:pathology*; D015588:Observer Variation; D010190:Pancreatic Neoplasms / Q000401:mortality / Q000473:pathology*; D012189:Retrospective Studies
chemical_list: D006657:Histones; D019394:Ki-67 Antigen
keywords: Grade; Ki67; Mitotic count; Pancreatic neuroendocrine tumor; Phosphohistone-H3; Vascular invasion