Ki-67 antigen in lung carcinoids/neuroendocrine tumors: from a proliferation marker to a clinical compass

INTRODUCTION: Ki-67 has extensively been studied in lung neuroendocrine tumors (NETs), including typical and atypical carcinoid, yet it has never been formally accepted into classification. Its clinical application was limited to the differential diagnosis toward neuroendocrine carcinomas and the characterization of carcinoids with increased proliferation rates. Recently, the International Association for the Study of Lung Cancer (IASLC) has released a novel grading-based classification, in which Ki-67 pays a central and decisional role. AREAS COVERED: This review examines the role of Ki-67 in lung NETs from three complementary perspectives (available English literature in PubMed, National Library of Medicine): (i) methodological issues, specimen types, grading-based classification, and molecular correlations; (ii) impact of statistical methods on study findings; (iii) clinical implications of a grading-based classification for diagnostic phase, hereditary syndromes, and therapeutic decision-making. EXPERT OPINION: The proposed grading-driven classification is likely to reshape established concepts and practices in the field of lung NETs, in future classifications. An awareness of the strengths and limitations of statistical methods used to define the distribution and significance of Ki-67 is essential for generating reliable, reproducible, and clinically meaningful evidence.