title: Grading the neuroendocrine tumors of the lung: an evidence-based proposal.
abstract: Lung neuroendocrine tumors are catalogued in four categories by the World Health Organization (WHO 2004) classification. Its reproducibility and prognostic efficacy was disputed. The WHO 2010 classification of digestive neuroendocrine neoplasms is based on Ki67 proliferation assessment and proved prognostically effective. This study aims at comparing these two classifications and at defining a prognostic grading system for lung neuroendocrine tumors. The study included 399 patients who underwent surgery and with at least 1 year follow-up between 1989 and 2011. Data on 21 variables were collected, and performance of grading systems and their components was compared by Cox regression and multivariable analyses. All statistical tests were two-sided. At Cox analysis, WHO 2004 stratified patients into three major groups with statistically significant survival difference (typical carcinoid vs atypical carcinoid (AC), P=0.021; AC vs large-cell/small-cell lung neuroendocrine carcinomas, P<0.001). Optimal discrimination in three groups was observed by Ki67% (Ki67% cutoffs: G1 <4, G2 4-<25, G3 ≥25; G1 vs G2, P=0.021; and G2 vs G3, P≤0.001), mitotic count (G1 ≤2, G2 >2-47, G3 >47; G1 vs G2, P≤0.001; and G2 vs G3, P≤0.001), and presence of necrosis (G1 absent, G2 <10% of sample, G3 >10% of sample; G1 vs G2, P≤0.001; and G2 vs G3, P≤0.001) at uni and multivariable analyses. The combination of these three variables resulted in a simple and effective grading system. A three-tiers grading system based on Ki67 index, mitotic count, and necrosis with cutoffs specifically generated for lung neuroendocrine tumors is prognostically effective and accurate.
authors.affiliation: Institute of Anatomic Pathology, Università Cattolica del Sacro Cuore - Policlinico A. Gemelli, Rome, Italy Service of Biometry and Clinical Epidemiology, Research Department, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy Service of Pathology, Centro Diagnostico Italiano, Milan, Italy Thoracic Unit, Department of Surgery, University of Parma, Parma, Italy Medical Oncology Unit, University Hospital of Parma, Parma, Italy Unit of Pathological Anatomy, Centre for Molecular and Translational Oncology, University Hospital, University of Parma, Parma, Italy Medical Oncology Unit of Respiratory Tract and Sarcomas, Department of Medical Oncology, European Institute of Oncology, Milan, Italy Division of Thoracic Surgery, European Institute of Oncology, Milan, Italy Department of Thoracic Surgery, Università Cattolica del Sacro Cuore - Policlinico A. Gemelli, Rome, Italy Division of Pathology, University of Turin at San Luigi Hospital, Orbassano, Torino, Italy Division of Thoracic Surgery, European Institute of Oncology, University of Milan School of Medicine, Milan, Italy Division of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy Department of Biomedical and Clinical Sciences 'Luigi Sacco', Università degli Studi, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Rindi
authors.forename: C
authors.initials: C
authors.lastname: Klersy
authors.forename: F
authors.initials: F
authors.lastname: Inzani
authors.forename: G
authors.initials: G
authors.lastname: Fellegara
authors.forename: L
authors.initials: L
authors.lastname: Ampollini
authors.forename: A
authors.initials: A
authors.lastname: Ardizzoni
authors.forename: N
authors.initials: N
authors.lastname: Campanini
authors.forename: P
authors.initials: P
authors.lastname: Carbognani
authors.forename: T M
authors.initials: TM
authors.lastname: De Pas
authors.forename: D
authors.initials: D
authors.lastname: Galetta
authors.forename: P L
authors.initials: PL
authors.lastname: Granone
authors.forename: L
authors.initials: L
authors.lastname: Righi
authors.forename: M
authors.initials: M
authors.lastname: Rusca
authors.forename: L
authors.initials: L
authors.lastname: Spaggiari
authors.forename: M
authors.initials: M
authors.lastname: Tiseo
authors.forename: G
authors.initials: G
authors.lastname: Viale
authors.forename: M
authors.initials: M
authors.lastname: Volante
authors.forename: M
authors.initials: M
authors.lastname: Papotti
authors.forename: G
authors.initials: G
authors.lastname: Pelosi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D018278:Carcinoma, Neuroendocrine / Q000145:classification / Q000401:mortality / Q000473:pathology*; D002648:Child; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D019317:Evidence-Based Medicine; D005260:Female; D006801:Humans; D007558:Italy / Q000453:epidemiology; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000032:analysis; D008137:Longitudinal Studies; D008175:Lung Neoplasms / Q000145:classification / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D014944:World Health Organization; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen