Neuroendocrine tumors of the larynx.

Neuroendocrine neoplasms of the larynx encompass five separate tumors: paraganglioma, typical carcinoid, atypical carcinoid, small cell carcinoma, and large cell neuroendocrine carcinoma. Many synonyms are employed, with well-, moderately, and poorly differentiated neuroendocrine carcinoma commonly applied to the middle three tumors (World Health Organization preferred terminology). Paraganglioma is an exceedingly uncommon neuroendocrine tumor in the larynx, as is large cell neuroendocrine carcinoma, and therefore these will not be further discussed. The most common laryngeal neuroendocrine tumor is the atypical carcinoid (moderately differentiated neuroendocrine carcinoma), which is a malignant epithelial tumor showing neuroendocrine histologic and immunohistochemical features. Small cell carcinoma is the next most common, while typical carcinoid (welldifferentiated neuroendocrine carcinoma) is very uncommon. All of these tumors affect men more often than women, usually in the older decades of life (fifth to seventh decades), and with a strong association with heavy tobacco use. Patients present with nonspecific clinical symptoms of hoarseness, dysphagia, and sore throat. In rare instances, aberrant hormone production by the tumor cells may result in a paraneoplastic syndrome. Outcome and management are different for each tumor type, but surgery is generally used for all, with chemotherapy added for the atypical carcinoid and small or large cell neuroendocrine carcinomas. Many patients present with advanced disease, and recurrences are common. The vast majority of tumors affect the supraglottic larynx, usually as a submucosal nodule or polypoid mass, but sometimes below an ulcerated mucosa in higher-grade tumors. Typical carcinoid grows in ribbons, nests, and festoons of relatively small to medium cells showing an intermediate nuclear-to-cytoplasmic ratio and round nuclei with delicate, salt-and-pepper nuclear chromatin distribution. Mitoses are inconspicuous. Atypical carcinoid cells grow in nests, cords, sheets, and trabeculae (figure 1) of round to spindled cells with granular cytoplasm surrounding nuclei with stippled to coarsely distributed chromatin (figure 2). Gland-like structures or rosettes may be seen. Tumor necrosis and 2 to 10 mitoses per 10 high-power fields are used to define the tumors and separate them from typical carcinoid and small cell carcinoma. Small cell carcinoma exhibits sheets, nests, and a trabecular arrangement of the neoplastic cells that are highly infiltrative, showing nuclei with granular chromatin and indistinct nucleoli. Nuclear molding, crush artifacts, necrosis, and high mitoses (>10 per 10 highpower fields) are easily identified (figure 3). The neoplastic cells are positive for a variety of cytokeratins and will react with at least one neuroendocrine marker (synaptophysin [figure 2] > CD56 > chromogranin). TTF-1 is variably expressed, although