Preface Knowledge of Pulmonary Neuroendocrine Tumors: Where Are We Now? Pier Luigi Filosso, MD, FECTS, FCCP Editor Neuroendocrine tumors (NETs) of the lung are regarded as a distinct clinical subgroup of lung cancer, which share particular morphologic, ul- trastructural, immunohistochemical, and molecu- lar characteristics. According to the 2004 World Health Organization classification of tumors, 1 they are categorized into 4 major groups, 2 ranging from the low-grade typical carcinoid (TC), to highly aggressive, poorly differentiated tumors (large-cell neuroendocrine carcinoma, LCNC, and small-cell lung cancer, SCLC). Amid them, an intermediate-grade neoplasm (atypical carcinoid, AC) is characterized by a greater aggressive biological behavior, compared to TC with a poorer 5-year survival and a higher ten- dency to lymph-nodal involvement at presenta- tion. TCs and ACs are categorized together as carcinoids; LCNC is considered a subgroup of large-cell carcinomas, and SCLC is an indepen- dent class of lung cancer. NETs derive from the pulmonary neuroendo- crine cells (PNECs), which are of endodermal origin, regardless of their phenotypic resem- blance to neurons. 3 In the postnatal phase and later, the PNEC system represents the lung stem cells niche, which is extremely important in the airway epithelial regeneration and carcino- genesis. 4,5 In the healthy adult, the PNECs distri- bution is quite permeating, with approximately 1 PNEC for every 2500 epithelial cells. Although PNECs are mostly solitary, sometimes they appear aggregate in innervated PNEC clusters, intended as neuroepithelial bodies (NEBs). 6 The precise PNEC biological function remains un- clear, as well as that of NEBs. Singular PNEC and NEB have a similar phenotype, because they are the site of adenosine, serotonin, and other amines storage, which play a very important role in normal lung development, growth, and repair. They have been considered to serve as airway chemoreceptors, responsive to hypoxia and thought to activate vagal nerves, partici- pating in breath regulation. 7 Neuroendocrine cell spread is also thought to be a rare preneoplastic condition: diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIP- NECH) is, in fact, characterized by a widespread peripheral airway PNEC and NEBs proliferation, while Tumorlet is a nodular neuroendocrine cell proliferation that measures less than 5 mm in diameter. DIPNECHs are also considered a sort of adaptive response in persons that live at high al- titudes, as well as a reactive response during lung injuries, the commonest of which are obliterative bronchiolitis and interstitial lung disease, and in patients with chronic cough. 8–10 Genetic abnormalities have been recently de- tected and proposed for a better classification of lung NETs. In particular, abnormal expression or loss of heterozygosity and point mutations of the p53 locus on chromosome 17p13 were seen in approximately 4% of TCs, 29% of ACs, and 80% Thorac Surg Clin 24 (2014) ix–xii http://dx.doi.org/10.1016/j.thorsurg.2014.05.005 1547-4127/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved. thoracic.theclinics.com Clinical Management of Neuroendocrine Tumors of the Lung