Large-Cell Neuroendocrine Carcinoma of the Lung

Felix G. Fernandez, MD; Richard J. Battafarano, MD, PhD


Cancer Control. 2006;13(4):270-275. 

In This Article

Abstract and Introduction


Background: Large-cell neuroendocrine carcinoma (LCNEC) of the lung displays morphologic and immunohistochemical characteristics common to neuroendocrine tumors and morphologic features of large-cell carcinomas. Because surgical resection of LCNEC in many series has been described with 5-year actuarial survival that is far worse than that reported for other histologic variants of non-small-cell lung cancer (NSCLC), considerable debate has emerged as to whether these tumors should be classified and treated as NSCLC or small-cell lung cancer.
Methods: The initial evaluation and diagnosis, tumor classification, surgical treatment, results of therapy, and long-term prognosis of patients with LCNEC based on our experience are discussed, and a review of the literature is presented.
Results: Patients with LCNEC are more likely to develop recurrent lung cancer and have shorter actuarial survival than patients with other histologic types of NSCLC, even in those with stage I disease.
Conclusions: Accurate differentiation of LCNEC from other types of NSCLC is important because it identifies those patients at highest risk for developing recurrent disease. Efforts to identify effective adjuvant therapies are needed to improve treatment outcomes with this aggressive type of lung cancer.


Neroendocrine tumors of the lung encompass a wide range of pathologic entities that display distinct biologic behaviors. In the 1970s, pulmonary neuroendocrine tumors were classified into three histologically defined categories. Typical carcinoid tumors, which metasta-size infrequently and have an excellent prognosis, are at one end of the spectrum. At the other extreme are small-cell carcinomas (SCCs), which frequently metastasize and have a dismal prognosis. Between these two extremes are atypical carcinoid tumors, first reported in 1972 by Arrigoni et al. [1] In 1991,Travis et al [2] were the first to propose large-cell neuroendocrine carcinoma (LCNEC) as a separate category of pulmonary neuroendocrine tumors, distinct from typical and atypical carcinoids and SCC. These tumors were described as having a cell size at least three times that of SCC, an organoid growth pattern, cellular palisading or rosette-like areas, a high mitotic rate, and a variably granular chromatin pattern. [3]

Dresler et al [4] classified the spectrum of neuroendocrine tumors on the basis of histologic characteristics and clinical behavior. Neuroendocrine tumors were classified as follows: grade I = classic typical carcinoid tumors, grade II = previously atypical carcinoids, and grade III = large-and small-cell types. However, in 1999, the World Health Organization International Association for Staging of Lung Cancer histologic classification of lung and pleural tumors grouped a number of histologic variants under the title "large-cell carcinoma (LCC)," including LCNEC, basaloid carcinoma, lymphoepithelioma-like carcinoma, and LCC with rhabdoid phenotype. [5] Such differences in classification have created confusion in the characterization of LCNEC of the lung.

Survival after resection of LCNEC appears to be substantially worse than for other non-small-cell lung cancer (NSCLC), resembling more the survival of SCC. Therefore, considerable debate has emerged as to whether these tumors should be classified and treated as NSCLC or considered together with SCC, given their aggressive behavior. The goal of this review is to clarify the existing literature on LCNEC to better classify this malignancy and help guide management decisions in terms of surgical resection and adjuvant therapy.


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