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Pulmonary Pathology Online

Pathology of Large Cell Neuroendocrine Carcinoma

Dr Sampurna Roy MD





Large cell neuroendocrine carcinoma (LCNEC) is a high-grade non–small-cell lung carcinoma (NSCLC)  and is part of the neuroendocrine spectrum of pulmonary tumours.


Large cell neuroendocrine carcinoma (LCNEC) of the lung displays morphologic and immunohistochemical characteristics common to neuroendocrine tumours and morphologic features of large-cell carcinomas.


Large cell neuroendocrine carcinoma is composed of cells with moderate amounts of cytoplasm and nuclei that show peripheral clumping of chromatin, a prominent nucleolus.


Much mitotic activity and extensive necrosis, as seen in any large cell carcinoma.


However, it is soon noticed that the tumour cells are arranged in well demarcated groups or cords with peripheral palisading.


This feature is reminiscent of a carcinoid pattern and the relationship to carcinoid is strengthened by shared immunocytochemical and ultrastructural features of neuroendocrine differentiation such as the presence neural cell adhesion molecule (CD56), chromogranin, synaptophysin and scanty dense-core granules.


Certain squamous cell carcinomas also show these neuroendocrine features -  these have been termed non-small cell carcinoma with neuroendocrine features.


Neuroendocrine differentiation can be demonstrated by electron microscopy or immunohistochemistry in 10-15% of non-small cell carcinomas of the lung despite an absence of morphological neuroendocrine features.

Differential diagnosis of large cell neuroendocrine carcinoma includes atypical carcinoid tumour but the organoid pattern of that tumour is not so well developed and the degree of atypia, mitotic activity and necrosis all far exceed those seen in an atypical carcinoid (which has between 2 and 10 mitoses per 2mm square [=10 high power fields] .

In general, large cell neuroendocrine carcinomas are tumours of middle-aged or elderly cigarette smokers that arise in central bronchi.

Despite the morphological evidence of neuroendocrine differentiation, ectopic hormone secretion is not a feature.

Patients with large cell neuroendocrine carcinomas have a significantly worse survival after resection than patients with large cell carcinomas, even in stage I disease.

Accurate differentiation of large cell neuroendocrine carcinoma from large cell carcinoma is important because it identifies those patients at highest risk for the development of recurrent lung cancer.

The clinical significance of these tumours has yet to be fully evaluated but their recognition is of potential therapeutic significance for their undoubted neuroendocrine nature links them to classic small cell carcinoma and it would be important if their metastases were similarly sensitive to chemotherapy.

However, reports available to date regarding their chemosensitivity are contradictory and as yet there have been no large scale, prospective, controlled trials of small cell chemotherapy for this subgroup of large cell carcinomas or for other non-small cell carcinomas showing neuroendocrine differentiation.

Furthermore, the clinical importance of neuroendocrine differentiation may diminish if a current trend towards treating all inoperable lung carcinomas with aggressive chemotherapy continues.

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Key Features:

-High-grade proliferation (mitotic rate of 10 mitoses per 10 high-power fields),

-Large aeas of necrosis,

-Neuroendocrine architecture, 

-Cytology of non-SCLC (NSCLC) 

-At least of one neuroendocrine marker other than neuron-specific enolase positive by immunohistochemistry.


Further reading:

Neuroendocrine carcinoma of unknown primary: a systematic review of the literature and a comparative study with other neuroendocrine tumors.

Large-cell neuroendocrine carcinoma of the lung: an aggressive neuroendocrine lung cancer.

Prognostic impact of large cell neuroendocrine histology in patients with pathologic stage Ia pulmonary non-small cell carcinoma.

Large-cell neuroendocrine carcinoma of the lung.

Large cell neuroendocrine carcinoma: an aggressive form of non-small cell lung cancer.

Large cell neuroendocrine carcinoma and large cell carcinomas with neuroendocrine morphology of the lung: prognosis after complete resection and systematic nodal dissection.

Large cell neuroendocrine carcinoma of the lung: a clinicopathologic study of eighty-seven cases.

Large cell neuroendocrine carcinoma of the lung: a histologic and immunohistochemical study of 22 cases.



Dr Sampurna Roy  MD

Consultant  Histopathologist (Kolkata - India)






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