Controversial issues and new discoveries in lung neuroendocrine tumors

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.