Abstract
Large cell neuroendocrine carcinoma of the lung (LCNEC) is a rare and highly aggressive type of lung cancer, with a complex biology that shares similarities with both small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). The prognosis of LCNEC is poor, with a median overall survival of 8–12 months. The diagnosis of LCNEC requires the identification of neuroendocrine morphology and the expression of at least one of the neuroendocrine markers (chromogranin A, synaptophysin or CD56). In the last few years, the introduction of next-generation sequencing allowed the identification of molecular subtypes of LCNEC, with prognostic and potential therapeutic implications: one subtype is similar to SCLC (SCLC-like), while the other is similar to NSCLC (NSCLC-like). Because of LCNEC rarity, most evidence comes from small retrospective studies and treatment strategies that are extrapolated from those adopted in patients with SCLC and NSCLC. Nevertheless, limited but promising data about targeted therapies and immune checkpoint inhibitors in patients with LCNEC are emerging. LCNEC clinical management is still controversial and standardized treatment strategies are currently lacking. The aim of this manuscript is to review clinical and molecular data about LCNEC to better understand the optimal management and the potential prognostic and therapeutic implications of molecular subtypes.
Highlights
Lung neuroendocrine tumors account for approximately 20% of all lung cancers [1]
In the last few years, the introduction of next-generation sequencing allowed the identification of molecular subtypes of large-cell neuroendocrine carcinoma (LCNEC), with prognostic and potential therapeutic implications: one subtype is similar to small-cell lung cancer (SCLC) (SCLC-like), while the other is similar to non-small-cell lung cancer (NSCLC) (NSCLC-like)
Because of its rarity and the peculiar biology, which is still largely not defined, patients with LCNEC should be addressed to tertiary centers with specific knowledge about rare neuroendocrine lung disease for a careful evaluation and treatment
Summary
Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a rare but highly aggressive tumor with neuroendocrine differentiation, representing about 3% of all lung cancers [2,3]. LCNEC was first identified as a distinct subtype of lung cancer by Travis et al and was classified by the World Health Organization (WHO) as a subtype of large-cell carcinoma (LCC), i.e., a neuroendocrine non-small-cell lung cancer (NSCLC) [4–6]. In 2015, the WHO classification grouped lung neuroendocrine neoplasms (NENs) into one category including four major subtypes and with distinct prognosis: typical carcinoid (TC) and atypical carcinoid (AC), which represents low- and intermediate-grade neuroendocrine tumors; small-cell lung cancer (SCLC) and LCNEC, which instead represent high-grade neuroendocrine carcinomas [7]. The close relationship between SCLC and LCNEC is based on common clinicopathologic characteristics, such as aggressive behavior, strong association with smoking, higher incidence in males, high proliferation rate, neuroendocrine gene expression and poor prognosis [8]. Patients with LCNEC and SCLC are typically heavy smokers, with a median age of 65 years and metastatic disease at diagnosis, as opposed to carcinoids patients who are generally younger, have no clear association with smoking and have a better prognosis
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