title: What clinicians are asking pathologists when dealing with lung neuroendocrine neoplasms?
abstract: Lung neuroendocrine tumors (NET) are currently classified in resection specimens according to four histological categories, namely typical carcinoid (TC), atypical carcinoid (AC), large-cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma (SCC). Diagnostic criteria have remained unchanged in the 2015 WHO classification, which has ratified the wide acceptance and popularity of such terminology in the pathologists׳ and clinicians׳ community. A unifying umbrella of NE morphology and differentiation has been recognized in lung NET, which has pushed to enter an unique box of invasive tumors along with diffuse idiopathic pulmonary NE cell hyperplasia (DIPNECH) as a pre-invasive lesion with a potential toward the development of carcinoids. However, uncertainties remain in the terminology of lung NET upon small samples, where Ki-67 antigen could play some role to avoid misdiagnosing carcinoids as high-grade NE tumors. Epidemiologic, clinical and genetic traits support a biological three-tier over a pathology four-tier model, according to which TC are low malignancy tumors, AC intermediate malignancy tumors and LCNEC/SCC high malignancy tumors with no significant differences in survival among them. Inconsistencies in diagnostic reproducibility, troubles in the therapy of AC and LCNEC, and limitations to histology within the same tumor category argue in favor of a global re-thinking of lung NET where a grading system could play a role. This review outlines three main key questions in the field of lung NET: (A) unbiased diagnoses, (B) the role of Ki-67 and tumor grading, and (C) management of predictive markers. Answers are still inconclusive, thus additional research is required to improve our understanding on lung NET.
authors.affiliation: Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian, 1, I-20133, Milan, Italy; Department of Biomedical and Clinical Sciences "Luigi Sacco", Università degli Studi, Milan, Italy. Electronic address: giuseppe.pelosi@unimi.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pelosi
authors.affiliation: Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian, 1, I-20133, Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Fabbri
authors.affiliation: Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian, 1, I-20133, Milan, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Cossa
authors.affiliation: Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian, 1, I-20133, Milan, Italy.
authors.forename: Angelica
authors.initials: A
authors.lastname: Sonzogni
authors.affiliation: Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian, 1, I-20133, Milan, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Valeri
authors.affiliation: Department of Pathology, University of Torino, Torino, Italy.
authors.forename: Luisella
authors.initials: L
authors.lastname: Righi
authors.affiliation: Department of Pathology, University of Torino, Torino, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Papotti
mesh_terms: D001706:Biopsy; D049109:Cell Proliferation; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D008175:Lung Neoplasms / Q000737:chemistry / Q000145:classification / Q000473:pathology* / Q000628:therapy; D060787:Neoplasm Grading; D055099:Neuroendocrine Cells / Q000737:chemistry / Q000473:pathology*; D018358:Neuroendocrine Tumors / Q000737:chemistry / Q000145:classification / Q000473:pathology* / Q000628:therapy; D011237:Predictive Value of Tests; D009626:Terminology as Topic
chemical_list: D019394:Ki-67 Antigen
keywords: Carcinoid; Diagnosis; Grading; Immunohistochemistry; Ki-67; Large cell; Molecular pathology; Neuroendocrine; Predictive; Prognosis; Small cell; Survival; Tumor