Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature. Neuroendocrine Tumors of the Larynx Neuroendocrine tumors of the larynx are rare, comprising only about 0.5% of laryngeal tumors. However, despite this rarity, they represent the most common non-squamous carcinomas of the larynx. Neuroendocrine tumors display a number of histologic, immunohistochemical and ultrastructural characteristics which reveal their neurosecretory nature and allow them to be grouped together. However, in terms of their pathology and clinical course, they represent a quite heterogenous group of neoplasms. To clear up this confusion, a number of classification systems have been devised. At the most basic level, a separation can be made between tumors which are neural in origin (paragangliomas) and those that are epidermoid (carcinoid, atypical carcinoid and small cell). The epidermoid carcinomas can be further divided. Woodruff et al suggested dividing neuroendocrine carcinomas of the larynx into two main types: small-cell and large-cell. Wenig and Gnepp suggested classifying these tumors into three groups: well-differentiated, moderately-differentiated, and poorly-differentiated neuroendocrine carcinomas. Finally, the World Health Organization's Classification of Tumors of the Upper Respiratory Tract has recommended a classification system which divides the neuroendocrine tumors into carcinoid, atypical carcinoid, and small cell carcinomas, with paragangliomas making up a fourth group. Approximately 400 cases of laryngeal neuroendocrine tumors have been reported. This represents about 0.5% of all laryngeal tumors. Among neuroendocrine tumors, small cell carcinomas are the most common, followed by paragangliomas and finally by carcinoids, with the typical carcinoid tumor being the most rare. There is a strong predilection for males with the exception of paragangliomas in which there is a male to female ration to 1 to 3. Smoking appears to be a major predisposing factor. The precursors of the small cell and carcinoid tumors are believed to be neuroendocrine cells called Kulchitsky's cells, which are normally found in laryngeal mucosa. These cells are part of the diffuse neuroendocrine system known as the APUD system (Amine Precursor Uptake and Decarboxylation). Alternatively, it has been proposed that the tumors may arise from nonendocrine, but pluripotential cells found in the seromucous gland-duct apparatus. Paragangliomas, on the other hand, are felt to arise from nests of paraganglion chief cells located within the larynx. These are part of the branchiomeric system of paraganglia, which include the precursors to glomus jugulare and glomus tympanicum tumors. In the larynx, these cells are found within two sets of paired paraganglia associated with the internal branch of the superior laryngeal nerve and the recurrent laryngeal nerve. Paragangliomas are vascular tumors composed of sustentacular and chief cells in an organoid, alveolar, or "zellballen" arrangement. Typical carcinoid tumors have an organoid or ribbon architecture in which the cells are uniform and small. These cells are usually devoid of cellular pleomorphism, mitoses or necrosis. Atypical carcinoids, on the other hand, manifest cellular pleomorphism, nuclear atypia, hyperchromatism, division figures and necrosis. Immunohistochemistry is used with increasing frequency to differentiate neuroendocrine tumors from other neoplasms which might have a similar appearance. Neuroendocrine tumors of the larynx present with symptoms similar to those of other laryngeal neoplasms. Hoarseness is by far the most common complaint, although pain, sometimes severe, frequently accompanies small cell tumors. In addition, the majority of small cell carcinomas present with neck masses at the time of diagnosis. Unlike neuroendocrine tumors found in other parts of the body, those found in the larynx are only very rarely responsible for paraneoplastic syndromes. Clinically, the neuroendocrine tumors display a broad spectrum of behavior, ranging from the nearly benign course of the paragangliomas to the aggressive, usually fatal course of the small-cell carcinomas. The malignant potential of paragangliomas has been a source of controversy. A rate of metastases of 325% has been commonly quoted in the literature. However, many investigators now believe that this figure may be inaccurate. Many cases of paragangliomas reported to have metastasized may in fact be missed diagnoses, probably representing under-diagnosed atypical carcinoids. Overall, the prognosis for this type of tumor is excellent. Typical carcinoids and atypical carcinoids represent progressively aggressive forms of neuroendocrine tumors. Prognosis of typical carcinoid is quite good. Patients rarely develop metastases, and those that do may live with disease for a number of years. Prognosis with atypical carcinoid was significantly worse. Metastases to neck nodes, skin, subcutaneous tissue and distant sites were common. The five- and ten-year survival rates are 48% and 30%, respectively. The clinical course of small-cell carcinoma of the larynx is even more dismal. Approximately 50% of patients present with palpable neck disease at the time of diagnosis. Seventy-three percent eventually develop distant metastases. The 2-year and 5-year survival is 16% and 5% respectively. Treatment of these tumors differs greatly depending on the type of lesion. Paragangliomas should be treated with conservative resection, because of their localized and generally non-aggressive nature. A chief consideration in excising these tumors is their extensively vascular makeup. For this reason, endoscopic removal is discouraged. Some authors have emphasized the use of preoperative angiography and embolization to reduce blood loss. Others argue that simple ligation of the superior thyroid artery can make angiography and embolization unnecessary. Recommendations for treatment of typical carcinoid are based on very few cases because of the tumor's rarity. Surgical excision is considered the treatment of choice. Conservative resection is encouraged as long as complete removal is obtained. Elective neck dissection has not been recommended due to the rare incidence of cervical metastases. Radiation and chemotherapy are not effective. More extensive surgical resection is required in the treatment of atypical carcinoid of the larynx. Wide margins of resection are required due to the propensity of the tumor to spread by way of perineural invasion. Routine neck dissection is encouraged due to the high incidence of subsequent cervical metastases. Unlike the other neuroendocrine tumors of the larynx, surgery has not been effective in the treatment of small cell carcinoma. The rapid progression from primary site to local and then distant metastases makes treatment aimed solely at the neck unlikely to be effective. The tumor should be considered to be disseminated at the time of diagnosis. Systemic chemotherapy and radiation to the neck is the currently recommended treatment for this tumor. Case Presentations A 49-year-old black, male smoker, with a history of alcoholism and cirrhosis of the liver, presented with a two-month history of an enlarging mass in the right neck and a one-month history of right-sided throat pain. Physical examination revealed a 4 cm x 5 cm firm, fixed mass in the right jugulodigastric area. Indirect laryngoscopy revealed an irregular, submucosal mass occupying the medial wall of the right pyriform sinus, with extension to the false vocal fold, and decreased mobility of the true vocal fold. A fine needle aspirate of the neck mass was consistent with small-cell carcinoma. A chest x-ray was negative for evidence of malignancy. Direct laryngoscopy was performed, and biopsy of the pyriform sinus lesion revealed small-cell carcinoma. 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Anaplastic small cell carcinoma of larynx. Ann Otol Rhinol Laryngol 1972;81:284-287. Overholt SM, Donovan DT, Schwartz MR, Alford BR. Neuroendocrine carcinomas of the larynx. (unpublished, 1993) Takeuchi K, Nishii S, Jin CS, et al. Anaplastic small cell carcinoma of the larynx. Auris Nasus Larynx 1989;16:127-132. Woodruff JM, Senie RT. Atypical carcinoid tumor of the larynx. A critical review of the literature. ORL J Otorhinolaryngol Relat Spec 1991;53:194-209. Grand Rounds Archive | Department Home page BCM Public | BCM Intranet | Privacy Notices | Contact BCM | BCM Site Map | ©2001-2006 Baylor College of Medicine
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