Lung cancer is the first cause of cancer mortality worldwide, and its early detection is currently the main available strategy to improve disease prognosis. While early diagnosis can be successfully achieved through tomography‐based population screenings in high‐risk individuals, simple methodologies are needed for effective cancer prevention programs. We developed a test, based on the detection of 34 microRNAs (miRNAs) from serum, that could identify patients with early stage non‐small cell lung carcinomas (NSCLCs) in a population of asymptomatic high‐risk individuals with 80% accuracy. The signature could assign disease probability accurately either in asymptomatic or symptomatic patients, is able to distinguish between benign and malignant lesions, and to capture the onset of the malignant disease in individual patients over time. Thus, our test displays a number of features of clinical relevance that project its utility in programs for the early detection of NSCLC. →See accompanying article http://dx.doi.org/10.1002/emmm.201100155

The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identify therapeutically relevant molecular groups of pulmonary carcinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirm the value ofOTPexpression levels for the prognosis and diagnosis of these diseases, and we unveil the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low- and high-grade lung neuroendocrine neoplasms.

In the lung, neoplasms with neuroendocrine (NE) morphology and differentiation encompass four histologically defined variants, namely typical carcinoid (TC), atypical carcinoid, large-cell NE carcinoma (LCNEC), and small-cell carcinoma (SCLC).¹ x 1 Travis, W, Brambilla, E, Muller-Hermelink, H, and Harris, C. Tumours of the Lung, Pleura, Thymus and Heart. IARC Press, Lyon; 2004 Google Scholar See all References ,² x 2 Travis, W, Colby, T, Corrin, B, Shimosato, Y, and Brambilla, E. Histological Typing of Lung and Pleural Tumours. Springer Verlag, Berlin, Heidelberg, New York; 1999 Crossref | Google Scholar See all References According to epidemiologic, genetic, and clinical data, pulmonary NE tumors may be assembled for prognosis and therapy purposes into a three-tier clinicopathological scheme, according to which TC are low-grade malignant tumors with long life expectation and usual surgical treatment; AC, intermediate-grade malignant tumors with more aggressive clinical course and multimodality therapy; and LCNEC and SCLC, high-grade malignant tumors with overlapping dismal prognosis and multimodality or exclusive medical treatment.¹ x 1 Travis, W, Brambilla, E, Muller-Hermelink, H, and Harris, C. Tumours of the Lung, Pleura, Thymus and Heart. IARC Press, Lyon; 2004 Google Scholar See all References ^{, 2} x 2 Travis, W, Colby, T, Corrin, B, Shimosato, Y, and Brambilla, E. Histological Typing of Lung and Pleural Tumours. Springer Verlag, Berlin, Heidelberg, New York; 1999 Crossref | Google Scholar See all References ^{, 3} x 3 Travis, WD, Gal, AA, Colby, TV et al. Reproducibility of neuroendocrine lung tumor classification. Hum Pathol. 1998; 29: 272–279 Abstract | Full Text PDF | PubMed | Scopus (194) | Google Scholar See all References ^{, 4} x 4 Travis, WD, Rush, W, Flieder, DB et al. Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid. Am J Surg Pathol. 1998; 22: 934–944 Crossref | PubMed | Scopus (582) | Google Scholar See all References ^{, 5} x 5 Gridelli, C, Rossi, A, Airoma, G et al. Treatment of pulmonary neuroendocrine tumours: state of the art and future developments. Cancer Treat Rev. 2013; 39: 466–472 Abstract | Full Text | Full Text PDF | PubMed | Scopus (38) | Google Scholar See all References ^{, 6} x 6 McMullan, DM and Wood, DE. Pulmonary carcinoid tumors. Semin Thorac Cardiovasc Surg. 2003; 15: 289–300 Abstract | Full Text | Full Text PDF | PubMed | Scopus (31) | Google Scholar See all References ^{, 7} x 7 Asamura, H, Kameya, T, Matsuno, Y et al. Neuroendocrine neoplasms of the lung: a prognostic spectrum. J Clin Oncol. 2006; 24: 70–76 Crossref | PubMed | Scopus (256) | Google Scholar See all References ^{, 8} x 8 Righi, L, Volante, M, Rapa, I et al. Mammalian target of rapamycin signaling activation patterns in neuroendocrine tumors of the lung. Endocr Relat Cancer. 2010; 17: 977–987 Crossref | PubMed | Scopus (63) | Google Scholar See all References

Neuroendocrine tumors of the lung (Lu-NETs) embrace a heterogeneous family of neoplasms classified into four histological variants, namely typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC). Defining criteria on resection specimens include mitotic count in 2 mm² and the presence or absence of necrosis, alongside a constellation of cytological and histological traits including cell size and shape, nuclear features and overall architecture. Clinically, TC are low-grade malignant tumors, AC intermediate-grade malignant tumors and SCLC/LCNEC high-grade malignant full-blown carcinomas with no significant differences in survival between them. Homologous tumors arise in the thymus that occasionally have some difficulties in differentiating from the lung counterparts when presented with large unresectable or metastatic lesions. Immunohistochemistry (IHC) helps refine NE diagnosis at various anatomical sites, particularly on small-sized tissue material, in which only TC and small cell carcinoma categories can be recognized easily on hematoxylin & eosin stain, while AC and LCNEC can only be suggested on such material. The Ki-67 labeling index effectively separates carcinoids from small cell carcinoma and may prove useful for the clinical management of a metastatic disease to help the therapeutic decision-making process. Although carcinoids and high-grade neuroendocrine carcinomas in the lung and elsewhere make up separate tumor categories on molecular grounds, emerging data supports the concept of secondary high-grade NETs arising in the preexisting carcinoids, whose clinical and biological relevance will have to be placed into the proper context for the optimal management of these patients. In this review, we will discuss the selected, recent literature with a focus on current issues regarding Lu-NET nosology, i.e., classification, derivation and tumor evolution.