Large cell neuroendocrine carcinoma of the lung
- Bonnie S Glisson, MD, FACP
Bonnie S Glisson, MD, FACP
- Professor and Associate Chair
- Department of Thoracic/Head and Neck Medical Oncology
- University of Texas MD Anderson Cancer Center
- Section Editors
- James R Jett, MD
James R Jett, MD
- Section Editor — Lung Cancer
- Professor of Medicine Emeritus
- National Jewish Health
- Rogerio C Lilenbaum, MD, FACP
Rogerio C Lilenbaum, MD, FACP
- Section Editor — Lung Cancer
- Yale Cancer Center
- Joseph S Friedberg, MD
Joseph S Friedberg, MD
- Section Editor — Thoracic Surgery
- Charles Reid Edwards Professor of Surgery
- University of Maryland
Large cell neuroendocrine carcinoma (LCNEC) is a rare pulmonary tumor, diagnosed based on high-grade features (>10 mitotic figures in 2 mm2 of viable tumor), and the presence of both neuroendocrine morphology as well as immunohistochemical evidence of neuroendocrine markers. However, application of the latter requirement to cytologic specimens and small biopsies, as opposed to resected tumors, is problematic [1-3]. LCNECs do not meet the criteria for the three better recognized neuroendocrine tumors (carcinoid, atypical carcinoid, and small cell carcinoma). Previously classified as a variant of large cell carcinoma, LCNEC is grouped with the pulmonary neuroendocrine carcinomas in the 2015 World Health Organization (WHO) classification. (See "Pathology of lung malignancies", section on 'Large cell neuroendocrine carcinoma'.)
CLINICAL PRESENTATION AND NATURAL HISTORY
The clinical presentation and natural history of LCNEC appear similar to the other high-grade neuroendocrine pulmonary tumor, small cell lung carcinoma (SCLC), with two exceptions: primary LCNECs tend to be located peripherally rather than centrally and presentation of LCNECs with early stage (I-II) disease is more common than for SCLC (approximately 25 percent versus less than 5 percent). Thus, patients with LCNEC more commonly undergo resection. Further, because LCNEC can be a difficult diagnosis based on needle aspirate or small biopsy, the diagnosis is frequently made post-resection.
Most studies indicate that survival is worse for LCNEC compared to non-small cell carcinoma and other large cell carcinomas, and similar to that of SCLC [1,3]. In a surveillance epidemiology and end results (SEER) database study of 1444 early stage patients who underwent resection only (no radiation therapy and no information regarding chemotherapy), a numerically worse four-year survival rate was observed in patients with SCLC, compared to LCNEC and other large cell carcinomas . However multivariate analysis demonstrated no significant difference in overall or lung cancer-specific survival between LCNEC and SCLC, nor between LCNEC and other large cell carcinomas. These data should not alter the general impression that LCNEC carries a relatively poor prognosis given the limitations of this analysis . (See "Overview of the risk factors, pathology, and clinical manifestations of lung cancer" and "Overview of the initial evaluation, treatment and prognosis of lung cancer".)
Molecular profiling of LCNEC suggests similarities between both small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC).
For example, targeted next-generation sequencing (241 genes) of 45 LCNEC resected tumors has demonstrated two major genomic signatures . Eighteen (40 percent) tumors possessed coalterations of TP53 and RB1 (18 of 43, 42 percent) and other alterations commonly found in SCLC, such as MYCL amplification, and were termed SCLC-like. Twenty-five (55 percent) tumors were devoid of coaltered TP53/RB1, and instead possessed mutations commonly seen in NSCLC including KRAS, STK11, and KEAP1, and differentiation marker expression seen in adenocarcinoma. However, this latter group, termed NSCLC-like, also had frequent mutations in NOTCH1-4, similar to SCLC. Although the number of cases is small, and confirmation of these findings in a larger dataset and prospective clinical trials are needed, molecular profiling of LCNEC may ultimately guide treatment choices in LCNEC.
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