Large cell carcinoma of the lung

Definition

An undifferentiated carcinoma lacking squamous, glandular or small cell features.

Epidemiology

Large cell carcinoma accounts for about 9% of primary lung carcinomas, of which about one third are large cell neuroendocrine carcinomas. All subtypes occur predominantly in smokers, except for lymphoepithelioma-like carcinoma7, which is most common in among the Chinese2,4,6.

Clinical features

A case associated with Eaton-Lambert syndrome has been reported8.

Radiology

Apart from basaloid carcinoma, most large cell carcinomas occur peripherally within the lung4.

Histopathology

These tumours are poorly differentiated and lack squamous, glandular or small cell components.

Variants:

Large cell neuroendocrine carcinoma (LCNEC)19: the neuroendocrine differentiation is suggested by organoid nesting, trabecular growth, rosetting or perilobular palisading. Cells are moderately large with abundant cytoplasm. Nucleoli are prominent. Mitotic rates exceed 11/10 HPF. Necrosis is common.
Combined large cell neuroendocrine carcinoma: a LCNEC combined with adenocarcinoma, squamous cell carcinoma or sarcomatoid carcinoma. If a small cell component is present, the tumour is classified as a combined small cell carcinoma.
Basaloid carcinoma1: there is a solid or trabecular pattern with peripheral palisading. Nuclear moulding is absent. The mitotic rate exceeds 15/10HPF. Squamous differentiation is lacking. Comedo necrosis is common.
Lymphoepithelioma-like carcinoma2,4,7: resembles that seen in the nasopharynx. It shows a syncytial growth pattern. Cells are large with large prominent nucleoli. Some cases show squamoid or glandular differentiation20. There is a marked lymphocytic infiltrate composed of mature lymphocytes, plasma cells and histiocytes, with some eosinophils and neutrophils. There may be intra-epithelial infiltration within small bronchi4. Rarely, there is amyloid intra-tumoral deposition4. Rare in the West, it is relatively common in China. Chinese6,20 but not Western cases are associated with EBV infection4.
Clear cell carcinoma: the cells are large with clear or foamy cytoplasm, variably containing glycogen. Clear cell tumours showing focal squamous or glandular differentiation should be classified as such12.
Large cell carcinoma with rhabdoid phenotype: at least 10% of cells must be of rhabdoid type with eosinophilic cytoplasmic globules3,5. These tumours frequently show neuroendocrine differentiation3.

Immunohistochemistry

See immunohistochemistry of malignant epithelial tumours of lung.

Large cell neuroendocrine carcinoma:

	CD56	usually positive
	Chromogranin	usually positive
	Synaptophysin	usually positive
	Definite positivity with one neuroendocrine marker is sufficient to establish the diagnosis of LCNEC
	TTF-1	50% of cases
	CK14	negative
	CK20	negative
	Transcription factor E2F1	5/1022

Basaloid carcinoma: Neuroendocrine markers are negative (in 10% of cases, one marker is positive in less than 20% of tumour cells). TTF-1 is negative.

Large cell carcinoma with rhabdoid phenotype: the cytoplasmic globules are positive for vimentin and cytokeratin3.

Differential diagnosis

Poorly differentiated squamous cell carcinoma. If a basaloid carcinoma includes a squamous component, it is to be regarded as a variant of squamous carcinoma.
Solid type adenocarcinoma
Atypical carcinoid: mitotic count less than 10/10 HPF
Basaloid carcinoma: small cell carcinoma
Lymphoepithelioma-like carcinoma: inflammatory pseudotumour, lymphoma, primary lymphoid hyperplasia.
Clear cell carcinoma: metastatic metastatic clear cell renal, thymic, thyroid or salivary gland carcinoma, clear cell variants of squamous cell carcinoma or adenocarcinoma.
Monotonous sheets of large cells resembling immunoblasts: DLBCL; LCA and cytokeratins differentiate. It has been suggested that large cell carcinomas of this morphology are aggressive13.

Prognosis

As for other non-small cell carcinomas of lung, dependent on performance status and TNM staging. The prognosis is worse than for other non small cell carcinomas18. Lymphoepithelioma-like carcinoma has a better prognosis7. Basaloid carcinoma is reported to have a prognosis inferior to that of poorly differentiated squamous cell carcinoma15.

The prognostic significance of neuroendocrine differentiation remains uncertain9,10. It has been proposed that large cell neuroendocrine carcinoma 14 or large cell carcinoma with large cell neuroendocrine features11 are more aggressive than is classical large cell carcinoma. Accurately staged stage I large cell carcinoma with neuroendocrine differentiation may have a relatively good prognosis21. Combined small cell carcinoma / large cell carcinoma has an inferior survival compared to pure large cell carcinoma16.

Lung tumours with a rhabdoid phenotype show aggressive behaviour and poor prognosis5, particularly if the proportion of rhabdoid cells exceeds 10%17.