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• Spread through air spaces is suggested to be invasion way of lung parenchyma. • Spread through air spaces has been described around lung neuroendocrine neoplasms. • Spread through air spaces may be made up by hyperplastic neuroendocrine cells. • Spread through air spaces is likely to be an ex vivo artifact due to tissue manipulation. Spread through air spaces (STAS) is a recently proposed invasion way of lung cancer, including neuroendocrine (NE) neoplasms. However, if this phenomenon is a real one or an artifact while manipulating lung specimens, it is still matter of debate. Three consecutive patients with newly diagnosed diffuse idiopathic pulmonary NE cell hyperplasia (DIPNECH) were reviewed for STAS. In well-fixed lung specimens, DIPNECH was seen to coexist with atypical carcinoid, bifocal typical carcinoid and adenocarcinoma in the three patients, respectively. While STAS was not observed at the growing edges of tumors, a few freely-floating aggregates of hyperplastic NE cells within air spaces were noticed to emanate from foci of NE hyperplasia and tumorlets and in intimate association with normal bronchiolar cells and erythrocytes to denote artifactual derivation upon tissue manipulation. Traveling of hyperplastic NE cells through air spaces is likely to artifactually occur via knife, surgeon or other way, thus challenging invasion by STAS. [ABSTRACT FROM AUTHOR]

Lung neuroendocrine (NE) tumors consist of four histologic subtypes, which are usually classified based on a three-tiered prognostic scheme. They are typical carcinoid (TC) as low-grade malignant tumors, atypical carcinoid (AD) as intermediate-grade malignant tumors, and large cell NE carcinoma (LCNEC) and small cell lung carcinoma (SCLC), both of which are high-grade malignant tumors. This three-tiered classification is based solely on histologic grounds and is a source of controversy especially when dealing with borderline or “gray zone” categories (TC vs. AC, AC vs. LCNEC, LCNEC and SCLC). In this review, controversial issues regarding the histologic classification will be discussed, and an innovative grading system that incorporates Ki-67 labeling index will be described. In addition, the recently discovered molecular alterations involved in TC/AC, as well as pathways involved in high-grade NE carcinomas, will be discussed in order to elucidate the differences in pathogenesis and biology between carcinoid tumors and high-grade NE carcinomas. [ABSTRACT FROM AUTHOR]

Immunoreactivity for fascin, an actin-bundling protein related to cell motility, has been reported in breast, ovary, pancreas, skin, and non-small cell carcinomas, and associated with more advanced disease stage and poorer prognosis. Data on pulmonary neuroendocrine (NE) tumors, however, are lacking. We evaluated the expression of fascin by immunohistochemistry—using two different monoclonal antibodies—in surgical specimens of pulmonary NE tumors of all the diverse histological types from 128 consecutive patients recruited between 1987 and 2001, and investigated its relationship with the presence of lymph node metastases. Overall, fascin immunoreactivity was detected in 5% of 38 typical carcinoids (TC), 35% of 23 atypical carcinoids (AC), 83% of 40 large-cell neuroendocrine carcinomas (LCNEC), and 100% of 27 small-cell lung carcinomas (SCLC) (P<0.001), Normal NE cells or hyperplastic NE tumorlets were consistently unreactive. No statistically significant differences in fascin immunoreactivity were found between the two antibodies. In TC and AC but not high-grade NE tumors, fascin immunoreactivity closely correlated with the occurrence of lymph node metastases, the pN class and the number of involved lymph nodes (P<0.001). It was also significantly associated with an increased proliferative activity (Ki-67 labeling index >5%) (P=0.020), and with either down-regulation or altered subcellular compartmentalization of E-cadherin (P<0.001) and CD99 (P=0.030), two cell adhesion complexes in pulmonary NE tumors. At multivariate analysis, only fascin emerged as an independent predictor of lymph node metastases in this tumor group (HR 30.28; 95% confidence intervals: 1.59–574.49; P=0.023). This study indicates that fascin immunoreactivity may identify subsets of pulmonary carcinoid patients with different metastatic potential to regional lymph nodes. Targeting the fascin pathway could be a novel therapeutic strategy of pulmonary carcinoids. [Copyright &y& Elsevier]

An estimated 20% to 30% of all neuroendocrine tumours originate in the bronchial tree and lungs. According to the 2015 World Health Organization categorization, these tumours are separated into four subtypes characterized by increasing biological aggressiveness: typical carcinoid, atypical carcinoid, large-cell neuroendocrine carcinoma and small-cell carcinoma. Although typical and atypical lung carcinoids account for less than 1–5% of all pulmonary malignancies, the incidence of these neoplasms has risen significantly in recent decades. Surgery is the treatment of choice for loco-regional disease but for advanced lung carcinoids there is no recognized standard of care and successful management requires a multidisciplinary approach. The aim of this review is to provide a useful guide for the clinical management of lung carcinoids. [ABSTRACT FROM AUTHOR]