Pathological Distinction of Pulmonary Large Cell Neuroendocrine Carcinoma from Small-Cell Lung Carcinoma Using Immunohistochemistry

Abstract

For many years, only two major categories of pulmonary neuroendocrine tumors were recognized: the carcinoid tumor and smallcell lung carcinoma (SCLC). In 1972, Arrigoni et al. (1972) proposed pathologic criteria for the atypical carcinoid tumor. Atypical carcinoids have more evident cytologic atypia, cellularity, focal necrosis, and increased mitotic activity (between 5 and 10 mitoses per 10 high-power fields) than typical carcinoid tumors, and the clinical aggressiveness of atypical carcinoid is less than that of SCLC. Since then, neuroendocrine tumors of the lung have been classified into three categories: typical carcinoid, atypical carcinoid, and SCLC. In recent years, it has become apparent that a large variety of pulmonary neuroendocrine tumors exist and that some tumors cannot be easily classified into one of these three categories. Several new categories have been proposed such as neuroendocrine carcinoma of intermediate sized cells, largecell neuroendocrine tumor of the lung, peripheral small-cell carcinoma of the lung resembling carcinoid tumor, and nonsmall cell lung carcinoma (NSCLC) with neuroendocrine features. In 1991, large cell neuroendocrine carcinoma (LCNEC) was proposed for the fourth high-grade neuroendocrine tumor of the lung (Travis et al., 1991). The World Health Organization classification in 1999, which has been further refined with associated molecular and genetic associations, describes LCNEC as a variant of large cell carcinoma, and tumors of the lung with neuroendocrine morphology have three grades of low-grade typical carcinoid, intermediate-grade atypical carcinoid, and high-grade LCNEC and SCLC. In this lung tumor classification schema, large cell carcinomas are classified into four types based on neuroendocrine morphology as determined by light microscopy, and neuroendocrine differentiation demonstrable by immunohistochemistry and/or electron microscopy as follows: (1) LCNEC has both neuroendocrine morphology and evidence of neuroendocrine differentiation with immunohistochemistry and/or electron microscopy; (2) large cell carcinoma with neuroendocrine differentiation (LCCND) lacks neuroendocrine