Lung
Neuroendocrine tumors
Large cell neuroendocrine carcinoma
Author: Roseann I. Wu, M.D., M.P.H.
Last author update: 1 October 2017
Last staff update: 6 March 2023 (update in progress)
Copyright: 2003-2023, PathologyOutlines.com, Inc.
PubMed Search: Large cell neuroendocrine carcinoma
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Electron microscopy description | Molecular / cytogenetics description | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1Cite this page: Wu R. Large cell neuroendocrine carcinoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lungtumorlargecellNE.html. Accessed June 2nd, 2023.
Definition / general
- Aggressive carcinoma composed of large malignant cells which display neuroendocrine features; characterized by high mitotic activity and necrosis
- Grouped with other neuroendocrine tumors in the 2015 WHO classification of lung tumors (J Thorac Oncol 2015;10:1243)
- Rosai: resembles non small cell carcinoma but on closer inspection has a hint of neuroendocrine architecture confirmed by special stains
- More likely to develop recurrent lung cancer and have shorter survival than patients with other histologic types of NSCLC, even in stage I disease (Cancer Control 2006;13:270)
- May coexist with other lung cancer such as adenocarcinoma and squamous cell carcinoma
Essential features
- High grade non small cell carcinoma with neuroendocrine morphology and immunohistochemical markers, characterized by > 10 mitoses / 2mm2 and extensive necrosis (J Thorac Oncol 2015;10:1243)
- Prognosis for large cell neuroendocrine carcinoma (LCNEC) is poor, similar to that of small cell carcinoma
- Should be distinguished from atypical carcinoid, basaloid squamous cell carcinoma and adenocarcinoma, although diagnosis can be difficult on small biopsies or cytology specimens
Terminology
- Large cell neuroendocrine carcinoma (LCNEC): proposed by Travis et al. in 1991 as distinct from small cell carcinoma (Am J Surg Pathol 1991;15:529)
- Large cell carcinoma with neuroendocrine morphology (LCNEM): if negative for neuroendocrine markers but shows neuroendocrine morphology (J Thorac Oncol 2015;10:1243)
- Combined LCNEC: also has components of adenocarcinoma (most common), squamous cell, giant cell or spindle cell carcinoma (Thorac Surg Clin 2014;24:257)
ICD coding
- Use code specific for location of tumor
- ICD-10: C34.90 - malignant neoplasm of unspecified part of unspecified bronchus or lung
Epidemiology
- Uncommon, ~3% of lung cancer
- Associated with older age, male gender, smoking
Sites
- Midzone or peripheral
Etiology
- Unclear clinical significance of preneoplastic lesions such as neuroendocrine cell hyperplasia and tumorlets (Endocrine 2015;50:315)
- Proposed model of histogenesis of lung neuroendocrine carcinomas, in view of similarities in the expression of primitive neural / neuroendocrine cell specific transcription factors (Pathol Int 2015;65:277)
Clinical features
- Asymptomatic nodule or chest pain, nonspecific flu-like symptoms, dyspnea, night sweats, carcinoid syndrome (J Thorac Oncol 2015;10:1133)
- Paraneoplastic syndrome less common than for small cell carcinoma
- 40% have regional metastases, 15 - 25% five year survival (Lung Cancer 2010;69:13)
Diagnosis
- Difficult to make specific diagnosis on small biopsy and cytology specimens
- Frequently recognized in cytology as non small cell lung cancer (NSCLC), not otherwise specified or as adenocarcinoma
- Neuroendocrine features by light microscopy and confirmation by immunohistochemical staining for neuroendocrine markers
Radiology description
- Nonspecific findings, indistinguishable from other NSCLC
- CT findings: peripherally located, expansively growing, irregular margin, with or without calcification, without bulky lymphadenopathy, infrequent cavitation (Clin Imaging 2007;31:379)
Radiology images
Images hosted on other servers:
PET / CT findings
Prognostic factors
- Worse prognosis than stage equivalent NSCLC (Semin Thorac Cardiovasc Surg 2006;18:206)
- Neuroendocrine marker profiles may assist the prediction of prognosis (Ann Thorac Surg 2015;99:983)
Case reports
- 64 year old woman diagnosed with LCNEC of the lung in an axillary lymph node (Int J Clin Exp Pathol 2013;6:1177)
- 65 year old man with combined LCNEC and giant cell carcinoma (J Cancer Res Ther 2012;8:445)
- 78 year old woman with LCNEC showing EGFR mutation and co-expression of adenocarcinoma markers (Multidiscip Respir Med 2013;8:47)
- 79 year old man with LCNEC and mucosa associated lymphoid tissue (MALT) lymphoma (Oncol Lett 2015;9:2068)
Treatment
- No standard; surgery and chemotherapy for early stage and chemotherapy for advanced stage disease (J Thorac Oncol 2015;10:1133, Lung Cancer 2010;69:13)
Gross description
- Circumscribed, necrotic, tanish red
Gross images
Contributed by Roseann Wu, M.D., M.P.H.
Peripheral LCNEC
Microscopic (histologic) description
- Neuroendocrine architecture may include organoid, nesting, palisading, trabecular, solid patterns and rosette-like structures
- >10 mitoses / 2 mm2, extensive / geographic necrosis
- Large cells (~3x size of small cell carcinoma) with abundant cytoplasm, variably coarse chromatin, nuclear pleomorphism, prominent nucleoli
- Larger tumor cells than atypical carcinoid, high nuclear grade, increased mitotic activity and necrosis (Arch Pathol Lab Med 2010;134:1628)
Microscopic (histologic) images
Contributed by Roseann Wu, M.D., M.P.H.
H&E
Chromogranin
Images hosted on other servers:
CD117
HER2
EGFR
Phosphohistone H3
Medullary tumor with no differentiation
Positive for AE1 / AE3,
synaptophysin, CD56,
KIT and TTF-1
Neck lymph node biopsy specimen
Prostate biopsy specimen
Cytology description
- Hypercellular, with numerous single, medium to large cells
- Three dimensional and variably sized groups
- Large, pleomorphic cells with irregular vesicular chromatin, prominent nucleoli, abundant cytoplasm, sharp cellular borders
- Naked nuclei abundant but with variable subset of cells showing evident cytoplasm
- Molding, mitoses, necrotic background
- Peripheral nuclear palisading; rosette-like structures (Cancer 2008;114:180)
Cytology images
Contributed by Roseann Wu, M.D., M.P.H.
Diff-Quik
Pap stained smear
Pap stained ThinPrep
Positive stains
- Neuroendocrine markers, focal to diffuse (chromogranin, synaptophysin, CD56), CD117 (60%), TTF1 (50%)
- Cytokeratins AE1 / AE3, Cam5.2, variable CK7
- High Ki67 (40 - 80%) helpful to differentiate from carcinoid tumors, especially in small biopsies (Semin Diagn Pathol 2015;32:469, J Thorac Oncol 2014;9:273)
- GLUT1 (74%, Mod Pathol 2009;22:633)
- Enhancer of zeste homolog 2 (EZH2): diffusely and strongly positive in all small cell carcinomas and large cell neuroendocrine carcinomas (Hum Pathol 2011;42:867)
Electron microscopy description
- Neurosecretory granules, occasional evidence of granular differentiation and intercellular junctions suggestive of squamous differentiation (Am J Surg Pathol 1991;15:529)
Molecular / cytogenetics description
- Inactivating mutations in TP53 and RB genes
- High frequencies of LOH and p53 (Cancer 1999;85:600)
- Mutations in the neurotrophic tyrosine receptor kinase genes (NTRK2 and NTRK3) in ~30% of LCNECs (Hum Mutat 2008;29:609)
Differential diagnosis
- Atypical carcinoid
- Basaloid squamous cell carcinoma: p40 positive
- Desmoplastic small round cell tumor
- Ewing sarcoma
- Poorly differentiated non small cell lung carcinoma
- Small cell carcinoma: considerable morphologic overlap but no prominent nucleoli
- Synovial sarcoma
Additional references
Board review style question #1
Pulmonary large cell neuroendocrine carcinoma, in contrast with small cell carcinoma, is associated with:
- > 10 mitoses / 2 mm2
- Extensive necrosis
- Nonsmokers
- Paraneoplastic syndrome
- Prominent nucleoli
Board review style answer #1
