Lung tumor
Neuroendocrine tumors
Large cell neuroendocrine carcinoma

Topic Completed: 1 October 2017

Minor changes: 22 October 2019

Copyright: 2003-2019,, Inc.

PubMed Search: (Large cell neuroendocrine carcinoma [title]) lung "loattrfree full text"[sb]

Roseann Wu, M.D., M.P.H.
Page views in 2019: 10,599
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Cite this page: Wu R. Large cell neuroendocrine carcinoma. website. Accessed August 14th, 2020.
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
  • 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
  • C34.90: malignant neoplasm of unspecified part of unspecified bronchus or lung
  • Uncommon, ~3% of lung cancer
  • Associated with older age, male gender, smoking
  • Midzone or peripheral
  • 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)
  • 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

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PET / CT findings

Prognostic factors
Case reports
Gross description
  • Circumscribed, necrotic, tanish red
Gross images

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Images contributed by Roseann Wu, M.D., MPH

Peripheral LCNEC

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Large masses with yellowish tan cut surface

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

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Images contributed by Roseann Wu, M.D., MPH



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Large nests with central necrosis

Large areas of geographic necrosis

Moderate to abundant quantity of pink cytoplasm




Phosphohistone H3

Metastases from lung primaries

Virtual slides

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Large cell neuroendocrine carcinoma

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

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Images contributed by Roseann Wu, M.D., MPH


Pap stained smear

Pap stained ThinPrep

Positive stains
Negative stains
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
Board review style question #1
Pulmonary large cell neuroendocrine carcinoma, in contrast with small cell carcinoma, is associated with:

  1. > 10 mitoses / 2 mm2
  2. Extensive necrosis
  3. Nonsmokers
  4. Paraneoplastic syndrome
  5. Prominent nucleoli
Board review answer #1
E. Prominent nucleoli
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