Large Cell Neuroendocrine Carcinoma of the Larynx: Definition of an Entity

Abstract

Laryngeal atypical carcinoids (AC/moderatelydifferentiated neuroendocrine carcinoma) are associated with moderately aggressive clinical behavior; however, a subset of tumors classified as AC have much greater aggressive potential. These tumors fulfill the proposed diagnostic criteria for pulmonary large cell neuroendocrine carcinoma, albeit in the larynx. In the current WHO classification, laryngeal large cell neuroendocrine carcinomas (LCNEC) are classified as variants of AC, whereas pulmonary LCNEC are classified as poorly-differentiated neuroendocrine carcinomas. Reported outcomes for pulmonary tumors support the separate classification of LCNEC. Five and ten year survival rates for pulmonary AC are 61-73, and 35-59%, respectively, while the 5-year survival rate for pulmonary LCNEC is as low as 30%. By extension, we postulate that the biologic potential of laryngeal LCNEC is similar to that of small-cell carcinoma (poorly-differentiated neuroendocrine carcinoma), and as such, warrants reclassification. The files of Barnes Jewish Hospital/Washington University were searched for the term ''neuroendocrine'' and the anatomic subsite larynx. Neuroendocrine carcinoma cases were evaluated using the WHO definitions for pulmonary AC and LCNEC; small cell carcinoma was excluded. Cases were also solicited from the larger head and neck pathology community. A literature search was also performed for cases of laryngeal neuroendocrine carcinoma, and cases which could be clearly classified as LCNEC by this scheme were captured as well. Six new cases plus four reported cases were identified which fulfill the WHO criteria for pulmonary LCNEC (eight men and two women). Nine patients presented at stage IV and 88% died of disease (DOD), 75 and 100% of these at 2 and 3 years, respectively. Laryngeal LCNEC is a rare entity, distinct from AC. We recommend that laryngeal tumors fulfilling WHO criteria for pulmonary LCNEC not be classified as variants of AC, but as variants of small cell carcinoma (poorly-differentiated neuroendocrine carcinoma) as they are associated with poorer outcome.

Update from the 4th Edition of the World Health Organization Classification of Head and Neck Tumours: What is New in the 2017 WHO Blue Book for Tumours of the Hypopharynx, Larynx, Trachea and Parapharyngeal Space

“…The terminology and classification of laryngeal neuroendocrine carcinomas have been changed and adjusted with recognition of the different biological behaviour and histological features of a particular entity in comparison with the classification used in previous edition [11][12][13]. Large cell neuroendocrine carcinoma, the main target of disagreement, which was previously grouped with atypical carcinoid/moderately differentiated NEC, grade II, is now transferred into a subtype of poorly differentiated NEC, grade III.…”

“…Particular attention is devoted to two histological subtypes of poorly differentiated NEC: small cell NEC (SmCNEC) and large cell NEC (LCNEC). LCNEC, which was grouped in the previous edition, WHO 2005, with atypical carcinoid/ moderately-differentiated neuroendocrine carcinoma, grade II, is now transferred to a subtype of poorly differentiated NEC, grade III, since these tumours show a specific morphology and are associated with a poorer outcome [11][12][13].…”

Neuroendocrine Neoplasms of the Head and Neck: Some Suggestions for the New WHO Classification of Head and Neck Tumors

“…This classification represented a significant step towards the standardization of diagnostic criteria of these neoplasms and although not explicitly stated, it incorporated most features of the 2004 WHO Classification for neuroendocrine carcinomas of the lung [6]. In recent years a consensus has been building in the head and neck pathology community that the current WHO Classification of Head and Neck Tumours does not adequately describe or define the clinicopathologic spectrum of NECs of the head and neck [7][8][9][10] with the most notable deficiency being the absence of a category for ''large cell neuroendocrine carcinoma'' (LC-NEC) [10][11][12]. In this short review, we visited some controversial areas in the pathology of neuroendocrine neoplasms of the head and neck which we believe should be addressed in any future WHO Classification of Head and Neck tumors.…”

Carcinosarcoma ex Non-Recurrent Pleomorphic Adenoma Composed of TTF-1 Positive Large Cell Neuroendocrine Carcinoma and Myofibrosarcoma: Apropos a Rare Case

“…The situation regarding salivary glands and LCNEC in relation to the WHO classification is analogous to that of the larynx, i.e. that the tumor seems to exist at these sites in reality but not in the WHO ''blue book'' [18][19][20].…”